Pyrazoline compounds

ABSTRACT

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.

FIELD OF THE INVENTION

The present invention comprises a class of pyrazoline compounds havingthe structure of Formula I and pharmaceutical compositions comprising acompound of Formula I. The present invention also comprises methods oftreating a subject by administering a therapeutically effective amountof a compound of Formula I to the subject. The present invention furthercomprises methods for making a compound of Formula I and correspondingintermediates.

BACKGROUND OF THE INVENTION

Hypertension affects about 20% of the adult population in developedcountries. In the adult population aged 60 years or older, thispercentage increases to about 60% to 70%. Hypertension also isassociated with an increased risk of other physiological complicationsincluding stroke, myocardial infarction, atrial fibrillation, heartfailure, peripheral vascular disease and renal impairment. Although anumber of anti-hypertensive drugs are available in variouspharmacological categories, the efficacy and safety of such drugs canvary from patient to patient.

Mineralocorticoid receptor antagonists are one class of drugs that canbe used to treat hypertension and/or related physiological complications(Jewell, C. W., et al., Cardiovascular & Hematological Agents inMedicinal Chemistry (2006) Vol. 4, pgs. 129-153). Mineralocorticoids,such as aldosterone, are involved in regulating salt and water balancein mammals. Activation of the mineralocorticoid receptor can inducehypertension and cause other detrimental cardiovascular andphysiological effects. Two mineralocorticoid receptor antagonists,spironolactone (ALDACTONE™) and eplerenone (INSPRA™), are presentlyavailable and indicated for the treatment of hypertension and heartfailure (Baxter, J. D., et al., Molecular and Cellular Endocrinology(2004) Vol. 217, pgs. 151-165).

The identification of additional compounds that are mineralocorticoidreceptor antagonists is desirable. Such compounds can be used to treatsubjects suffering from or susceptible to hypertension and/or relatedphysiological problems and further expand the range of treatment optionsavailable for such subjects. Both spironolactone and eplerenone have asteroidal structure. The present invention is particularly directed tomineralocorticoid receptor antagonists that are non-steroidal compounds.Use of a non-steroidal mineralocorticoid receptor antagonist potentiallyprovides certain advantages over a steroidal mineralocorticoid receptorantagonist including, e.g., further improvement in selectivity withrespect to the sex hormone receptors; less complex and costly chemicalsynthesis; and the like.

Non-steroidal compounds useful as mineralocorticoid receptor antagonistshave been reported in the literature. For example:

WO 06/076202 (published Jul. 20, 2006) reports a class of imidazolecarboxamides as mineralocorticoid receptor antagonists.

WO 06/012642 (published Feb. 2, 2006) reports a class of pyrrolecarboxamides as mineralocorticoid receptor antagonists.

WO 04/052847 (published Jun. 24, 2004) reports a class ofdibenzosuberanes as mineralocorticoid receptor antagonists.

WO 05/066161 (published Jul. 21, 2005) reports a class ofdibenzosuberanes as mineralocorticoid receptor antagonists.

WO 03/078394 (published Sep. 25, 2003) reports a class of 3,3-bisaryloxindoles as mineralocorticoid receptor antagonists.

WO 05/097118 (published Oct. 20, 2005) reports a class of4-aryl-1,4-dihydropyridines as mineralocorticoid receptor antagonists.

WO 04/067529 (published Aug. 12, 2004) reports a class of 3-benzylindoles as mineralocorticoid receptor antagonists.

WO 06/077821 (published Jul. 27, 2006) reports classes ofbenzoxazinethiones and tetrahydroquinolines as mineralocorticoidreceptor antagonists.

WO 06/010142 (published Jan. 26, 2006) reports a class of arylbenzoxazinones/thiones as mineralocorticoid receptor antagonists.

SUMMARY OF THE INVENTION

In one embodiment, the invention comprises a class of compounds havingthe structure of Formula I:

and the pharmaceutically acceptable salts thereof; wherein R¹, R²,R^(3A), R^(3B), R⁴, R⁵, R⁶, R⁷, R⁸, and X are as defined in the DetailedDescription of the Invention.

In another embodiment, the invention comprises a pharmaceuticalcomposition comprising a compound having the structure of Formula I, ora pharmaceutically acceptable salt thereof; and apharmaceutically-acceptable carrier.

In another embodiment, the invention comprises a pharmaceuticalcomposition comprising a compound having the structure of Formula I, ora pharmaceutically acceptable salt thereof; one or more additionalpharmaceutically active compounds; and a pharmaceutically-acceptablecarrier.

In another embodiment, the invention comprises methods of treating acondition in a subject by administering to a subject a therapeuticallyeffective amount of a compound having the structure of Formula I. Theconditions that can be treated in accordance with the present inventioninclude cardiovascular conditions (including hypertension and heartfailure), renal conditions, liver conditions, vascular conditions,retinopathy, neuropathy (including peripheral neuropathy),insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction,and the like.

In another embodiment, the invention comprises methods of treating acondition in a subject by administering a compound having the structureof Formula I in combination with another pharmaceutically activecompound. The conditions that can be treated in accordance with thepresent invention include cardiovascular conditions (includinghypertension and heart failure), renal conditions, liver conditions,vascular conditions, retinopathy, neuropathy (including peripheralneuropathy), insulinopathy, edema, endothelial dysfunction, baroreceptordysfunction, and the like.

In another embodiment, the invention comprises use of a compound havingthe structure of Formula I, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment of acondition in a subject. The conditions that can be treated in accordancewith the present invention include cardiovascular conditions (includinghypertension and heart failure), renal conditions, liver conditions,vascular conditions, retinopathy, neuropathy (including peripheralneuropathy), insulinopathy, edema, endothelial dysfunction, baroreceptordysfunction, and the like.

In another embodiment, the invention comprises methods for making acompound having the structure of Formula I, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the invention comprises intermediates useful inmaking a compound having the structure of Formula I, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

This detailed description of embodiments is intended only to acquaintothers skilled in the art with Applicants' invention, its principles,and its practical application so that others skilled in the art mayadapt and apply the inventions in their numerous forms, as they may bebest suited to the requirements of a particular use. These inventions,therefore, are not limited to the embodiments described in thisspecification, and may be variously modified.

A. ABBREVIATIONS AND DEFINITIONS

As used in reference to ¹H NMR, the symbol “δ” refers to a ¹H NMRchemical shift.

As used in reference to ¹H NMR, the abbreviation “br” refers to a broad¹H NMR signal.

As used in reference to ¹H NMR, the abbreviation “d” refers to a doublet¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “dd” refers to adoublet of doublets ¹H NMR peak.

The abbreviation “HRMS” refers to High Resolution Mass Spectrocopy(electrospray ionisation positive scan).

The abbreviation “m/z” refers to a Mass spectrum peak.

As used in reference to ¹H NMR, the abbreviation “m” refers to amultiplet ¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “q” refers to a quartet¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “s” refers to a singlet¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “t” refers to a triplet¹H NMR peak.

The term “alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent containing only carbon andhydrogen) containing in one embodiment, from about one to about twentycarbon atoms; in another embodiment from about one to about twelvecarbon atoms; in another embodiment, from about one to about ten carbonatoms; in another embodiment, from about one to about eight carbonatoms; in another embodiment, from about one to about six carbon atoms;in another embodiment, from about three to about six carbons; in anotherembodiment, from about one to about 4 carbons; in another embodiment,from about one to about three carbons; and in another embodiment, fromabout one to about two carbon atoms. Examples of such substituentsinclude methyl, ethyl, propyl (including n-propyl and isopropyl), butyl(including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl,iso-amyl, hexyl and the like.

The term “alkenyl” refers to a linear or branched-chain hydrocarbylsubstituent containing one or more double bonds and from about two toabout twenty carbon atoms; in another embodiment, from about two toabout twelve carbon atoms; in another embodiment, from about two toabout six carbon atoms; in another embodiment, from about three to aboutsix carbons; and in another embodiment, from about two to about fourcarbon atoms. Examples of alkenyl include ethenyl (also known as vinyl),allyl, propenyl (including 1-propenyl and 2-propenyl) and butenyl(including 1-butenyl, 2-butenyl and 3-butenyl). The term “alkenyl”embraces substituents having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “benzyl” refers to methyl radical substituted with phenyl.

The term “cycloalkyl” refers to a saturated carbocyclic substituenthaving three to about fourteen carbon atoms. In another embodiment, acycloalkyl substituent has three to about eight carbon atoms. In anotherembodiment, a cycloalkyl substituent has from three to about sixcarbons; in another embodiment, from three to about four carbons.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term “aryl” refers to a carbocyclic aromatic system containing one,two or three rings wherein such rings may be attached together in apendent manner or may be fused. The term “aryl” refers to aromaticsubstituents such as phenyl, naphthyl and anthracenyl.

The term “arylalkyl” refers to alkyl substituted with aryl.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, etc.) is indicated by the prefix “C_(x)—C_(y)—,” wherein x is theminimum and y is the maximum number of carbon atoms in the substituent.Thus, for example, “C₁-C₆-alkyl” refers to an alkyl substituentcontaining from 1 to 6 carbon atoms. Illustrating further,C₃-C₆-cycloalkyl refers to saturated carbocyclyl containing from 3 to 6carbon ring atoms.

The terms “hydroxy” and “hydroxyl” each refer to —OH. Hydroxyl may beused alone to indicate the substituent, as in “a hydroxyl group.” Whenused in combination with another term(s), the prefix “hydroxy” indicatesthat the substituent to which the prefix is attached is substituted withone or more hydroxyl substituents. Compounds bearing a carbon to whichone or more hydroxyl substituents include, for example, alcohols, enolsand phenol.

The term “hydroxyalkyl” refers to an alkyl that is substituted with atleast one hydroxy substituent. Examples of hydroxyalkyl includehydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term “alkylamino” refers to an amino group, wherein at least onealkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.Examples of alkylamino substituents include monoalkylamino such asmethylamino (exemplified by the formula —NH(CH₃)), and dialkylamino suchas dimethylamino, (exemplified by the formula —N((CH₃)₂).

The term “aminocarbonyl” refers to —C(O)—NH₂.

The term “halogen” refers to fluorine, chlorine, bromine, or iodine(which may be depicted as —I). In one embodiment, the halogen ischlorine. In another embodiment, the halogen is fluorine.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogensubstituents. For example, haloalkyl refers to an alkyl that issubstituted with at least one halogen substituent. Where there is morethan one hydrogen replaced with a halogen, the halogen replacements maybe the identical or different. Examples of haloalkyls includechloromethyl, dichloromethyl, difluorochloromethyl,dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl,pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.Illustrating further, “haloalkoxy” refers to an alkoxy that issubstituted with at least one halogen substituent. Examples ofhaloalkoxy substituents include chloromethoxy, 1-bromoethoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as“perfluoromethyloxy”), and 2,2,2-trifluoroethoxy. It should berecognized that if a substituent is substituted by more than one halogensubstituent, those halogen substituents may be identical or different(unless otherwise stated).

The term “oxo” refers to ═O.

The term “oxy” refers to an ether substituent, and may be depicted as—O—.

The term “alkoxy” refers to an alkyl linked to an oxygen atom, which mayalso be represented as —O—R, wherein the R represents the alkyl group.Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.

The term “alkylcarbonyl” refers to —C(O)-alkyl. For example,“ethylcarbonyl”. Examples of other alkylcarbonyl include methylcarbonyl,propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.

The term “aminoalkylcarbonyl” refers to —C(O)-alkyl-NH₂. For example,“aminomethylcarbonyl”.

The term “alkoxycarbonyl” refers to —C(O)—O-alkyl. For example,“ethoxycarbonyl”. Examples of other alkoxycarbonyl includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, and hexyloxycarbonyl. In another embodiment, where thecarbon atom of the carbonyl is attached to a carbon atom of a secondalkyl, the resulting functional group is an ester.

The terms “thio” and “thia” refer to a divalent sulfur atom and such asubstituent may be depicted as —S—. For example, a thioether isrepresented as “alkyl-thio-alkyl” or, alternatively, alkyl-5-alkyl.

The term “thiol” refers to a sulfhydryl substituent, and may be depictedas —SH.

The term “sulfonyl” refers to —S(O)₂—. Thus, for example,“alkyl-sulfonyl-alkyl” refers to alkyl-S(O)₂-alkyl. Examples ofalkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

The term “aminosulfonyl” refers to —S(O)₂—NH₂.

The term “sulfinyl” refers to —S(O)—. Thus, for example,“alkylsulfinylalkyl” or “alkylsulfoxidoalkyl” refers toalkyl-S(O)-alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl,ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.

The term “spiro compound” refers to two or three rings which have onlyone atom in common and the two or three rings are not linked by abridge. The common ring atom is designated as the spiro atom. A spirocompound may comprise one or more heteroatoms; such a compound fallswithin the definition of heterocyclyl, infra.

The term “heterocyclyl” refers to a saturated, partially saturated, orcompletely unsaturated ring structure containing a total of 3 to 14 ringatoms. At least one of the ring atoms is a heteroatom (i.e., oxygen,nitrogen, or sulfur), with the remaining ring atoms being independentlyselected from the group consisting of carbon, oxygen, nitrogen, andsulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude, without limitation, azetidinyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thiofuranyl, dihydrothiofuranyl,tetrahydrothiofuranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, oxathiazolyl, oxadiazolyl,furazanyl, oxatriazolyl (including 1,2,3,4-oxatriazolyl or1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl,1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiolanyl,pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl,pyridinyl (also known as “pyridyl”), piperidinyl, pyridazinyl,pyrimidinyl (also known as “pyrimidyl”), pyrazinyl, piperazinyl,triazinyl, oxazinyl, oxazolidinyl, isoxazolidinyl, oxathiazinyl,oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

A heterocyclyl may also comprise 2 or 3 rings fused together, wherein atleast one such ring contains at least one heteroatom as a ring atom(e.g., nitrogen, oxygen, or sulfur). Examples of 2-fused-ringheterocyclyls include, without limitation, indolizinyl, 4H-quinolizinyl,purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl,phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl,benzothiopyranyl, benzoxazolyl, benzodioxolyl, benzodioxanyl,benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl,benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, andacridinyl. Additional examples of fused ring heterocyclyls includetetrahydrodioxolopyrrolyl and tetrahydrotriazolopyrazinyl.

The term “heteroaryl” refers to an aromatic heterocyclyl containing from5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fusedrings. Examples of heteroaryl substituents include 6-membered ringsubstituents such as pyridinyl (also known as “pyridyl”), pyrazyl,pyrimidinyl (also know as “pyrimidyl”), and pyridazinyl; 5-membered ringsubstituents such as triazolyl, imidazyl, furanyl, thiofuranyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl andisothiazolyl; 6/5-membered fused ring substituents such asbenzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl; and6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl,and quinazolinyl.

The term “heterocyclylalkyl” refers to alkyl substituted with aheterocyclyl.

The term “heterocycloalkyl” refers to a fully saturated heterocyclyl.

A substituent is “substitutable” if it comprises at least one carbon,sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogenatoms. Thus, for example, hydrogen, halogen, and cyano do not fallwithin this definition.

If a substituent is described as being “substituted,” a non-hydrogensubstituent is in the place of a hydrogen substituent on a carbon ornitrogen of the substituent. Thus, for example, a substituted alkylsubstituent is an alkyl substituent wherein at least one non-hydrogensubstituent is in the place of a hydrogen substituent on the alkylsubstituent. To illustrate, monofluoroalkyl is alkyl substituted with afluoro substituent, and difluoroalkyl is alkyl substituted with twofluoro substituents. It should be recognized that if there is more thanone substitution on a substituent, each non-hydrogen substituent may beidentical or different (unless otherwise stated).

If a substituent is described as being “optionally substituted,” thesubstituent may be either (1) not substituted, or (2) substituted. If acarbon of a substituent is described as being optionally substitutedwith one or more of a list of substituents, one or more of the hydrogenson the carbon (to the extent there are any) may separately and/ortogether be replaced with an independently selected optionalsubstituent. If a nitrogen of a substituent is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogens on the nitrogen (to the extent there are any)may each be replaced with an independently selected optionalsubstituent.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably.

If a group of substituents are collectively described as beingoptionally substituted by one or more of a list of substituents, thegroup may include: (1) unsubstitutable substituents, (2) substitutablesubstituents that are not substituted by the optional substituents,and/or (3) substitutable substituents that are substituted by one ormore of the optional substituents.

If a substituent is described as being optionally substituted with up toa particular number of non-hydrogen substituents, that substituent maybe either (1) not substituted; or (2) substituted by up to thatparticular number of non-hydrogen substituents or by up to the maximumnumber of substitutable positions on the substituent, whichever is less.Thus, for example, if a substituent is described as a heteroaryloptionally substituted with up to 3 non-hydrogen substituents, then anyheteroaryl with less than 3 substitutable positions would be optionallysubstituted by up to only as many non-hydrogen substituents as theheteroaryl has substitutable positions. To illustrate, tetrazolyl (whichhas only one substitutable position) would be optionally substitutedwith up to one non-hydrogen substituent. To illustrate further, if anamino nitrogen is described as being optionally substituted with up to 2non-hydrogen substituents, then the nitrogen will be optionallysubstituted with up to 2 non-hydrogen substituents if the amino nitrogenis a primary nitrogen, whereas the amino nitrogen will be optionallysubstituted with up to only 1 non-hydrogen substituent if the aminonitrogen is a secondary nitrogen.

A prefix attached to a multi-moiety substituent only applies to thefirst moiety. To illustrate, the term “alkylcycloalkyl” contains twomoieties: alkyl and cycloalkyl. Thus, the C₁-C₆— prefix onC₁-C₆-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkylcontains from 1 to 6 carbon atoms; the C₁-C₆-prefix does not describethe cycloalkyl moiety. To illustrate further, the prefix “halo” onhaloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkylsubstituent is substituted with one or more halogen substituents. Ifhalogen substitution may alternatively or additionally occur on thealkyl moiety, the substituent would instead be described as“halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Andfinally, if the halogen substitution may only occur on the alkyl moiety,the substituent would instead be described as “alkoxyhaloalkyl.”

When a substituent is comprised of multiple moieties, unless otherwiseindicated, it is the intention for the final moiety to serve as thepoint of attachment to the remainder of the molecule.

For example, in a substituent A-B-C, moiety C is attached to theremainder of the molecule. In a substituent A-B-C-D, moiety D isattached to the remainder of the molecule. Similarly, in a substituentaminocarbonylmethyl, the methyl moiety is attached to the remainder ofthe molecule. In a substituent trifluoromethylaminocarbonyl, thecarbonyl moiety is attached to the remainder of the molecule.

Parentheses may be used to describe a substituent when multiple firstmoieties are intended to substitute a single second moiety. In asubstituent (hydroxymethyl)(ethyl)piperidinyl, both the hydroxymethylmoiety and ethyl moiety are directly attached to the piperidinyl moiety.Alternatively, if a substituent is not substitutable, no parentheses arenecessary. For example, a “fluorochloromethane” describes a carbon atombonded directly to a chlorine, a fluorine, and two hydrogen atoms.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

The term “pharmaceutically acceptable carrier” refers to a carrier thatis compatible with the other ingredients of the composition and is notdeleterious to the subject. Such carriers may be pharmaceuticallyacceptable material, composition or vehicle, such as a liquid or solidfiller, diluent, excipient, solvent or encapsulating material, involvedin carrying or transporting a chemical agent. The preferred compositiondepends on the method of administration.

The terms “prevent,” “prevention” or “preventing” refer to eitherpreventing the onset of a preclinically evident condition altogether orpreventing the onset of a preclinical evident stage of a condition in asubject. Prevention includes, but is not limited to, prophylactictreatment of a subject at risk of developing a condition.

The term “therapeutically effective amount” refers to that amount ofdrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system or animal that is being sought by aresearcher or clinician.

The term “treatment” (and corresponding terms “treat” and “treating”)includes palliative, restorative, and preventative treatment of asubject. The term “palliative treatment” refers to treatment that easesor reduces the effect or intensity of a condition in a subject withoutcuring the condition. The term “preventative treatment” (and thecorresponding term “prophylactic treatment”) refers to treatment thatprevents the occurrence of a condition in a subject. The term“restorative treatment” refers to treatment that halts the progressionof, reduces the pathologic manifestations of, or entirely eliminates acondition in a subject.

B. COMPOUNDS

The present invention is directed to a class of compounds (includingpharmaceutically acceptable salts and tautomers of the compounds),wherein the compounds have the structure of Formula I:

wherein:

X is selected from the group consisting of —CH₂— and —O—;

R¹ is selected from the group consisting of alkyl, cycloalkyl,cycloalkenyl, phenyl, and heterocyclyl; wherein the heterocyclylsubstituent is a five- or six-membered ring heterocyclyl comprising atleast one ring heteroatom selected from oxygen, sulfur and nitrogen; andwherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, and heterocyclylsubstituents may be optionally substituted with one or more substituentsindependently selected from the group consisting of hydroxy, halogen,alkyl, and haloalkyl;

R² is selected from the group consisting of hydrogen and alkyl;

R^(3A) and R^(3B) are independently selected from the group consistingof hydrogen and alkyl;

R⁴, R⁶, and R⁷ are independently selected from the group consisting ofhydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, and alkoxy;

R⁵ is selected from the group consisting of hydrogen, —(CH₂)_(m)OR⁵⁰,—(CH₂)_(m)C(O)R⁵⁰, —(CH₂)_(m)C(O)OR⁵⁰, —(CH₂)_(m)C(O)NR⁵¹R⁵²,—(CH₂)_(m)NR⁵¹R⁵², —(CH₂)_(m)N(R⁵¹)C(O)R⁵², and —(CH₂)_(m)S(O)_(m)R⁵⁰;

m is 0, 1, 2, 3, 4, 5, or 6;

n is 0, 1, or 2;

R⁵⁰ is selected from the group consisting of hydrogen and alkyl;

R⁵¹ and R⁵² are independently selected from the group consisting ofhydrogen and alkyl; or R⁵¹ and R⁵² together with the nitrogen to whichthey are attached form a five- or six-membered ring heterocyclyl;wherein the R⁵⁰, R⁵¹ and R⁵² alkyl substituents and the R⁵¹/R⁵²heterocyclyl substituent may be independently and optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, pyrrolidinyl, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵;

p is 0, 1, or 2;

R⁵³ is selected from the group consisting of hydrogen, alkyl, haloalkyl,hydroxyalkyl, and carboxyalkyl;

R⁵⁴ and R⁵⁵ are independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, hydroxyalkyl, and carboxyalkyl; or R⁵⁴ andR⁵⁵ together with the nitrogen to which they are attached form a five-or six-membered ring heterocyclyl;

R⁵⁶ is selected from the group consisting of hydrogen and alkyl; and

R⁸ is selected from the group consisting of phenyl, pyridinyl andpyrimidinyl; wherein the phenyl, pyridinyl and pyrimidinyl substituentsmay be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, carboxy, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl,carboxyalkyl, alkoxy, haloalkoxy, cyanoalkoxy, amino, alkylamino,dialkylamino, and alkoxycarbonyl.

In one embodiment of the compounds of Formula I, R^(3A), R^(3B), R⁴, R⁶and R⁷ are each hydrogen. In another embodiment, R², R^(3A), R^(3B), R⁴,R⁶ and R⁷ are each hydrogen. In still another embodiment, X is —CH₂—;and R², R^(3A), R^(3B), R⁴, R⁶ and R⁷ are each hydrogen. In stillanother embodiment, X is —O—; and R², R^(3A), R^(3B), R⁴, R⁶ and R⁷ areeach hydrogen.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; and R¹ is selected from the groupconsisting of cycloalkyl and phenyl; wherein the R¹ cycloalkyl andphenyl substituents may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, alkyl, and haloalkyl.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; and R⁸ is phenyl; wherein the R⁸ phenylsubstituent may be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, carboxy, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl,carboxyalkyl, alkoxy, haloalkoxy, cyanoalkoxy, amino, alkylamino,dialkylamino, and alkoxycarbonyl. In still another embodiment, the R⁸phenyl substituent may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, and alkyl.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; and R⁸ is pyridinyl; wherein the R⁸pyridinyl substituent may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, carboxy, alkyl, haloalkyl, cyanoalkyl,hydroxyalkyl, carboxyalkyl, alkoxy, haloalkoxy, cyanoalkoxy, amino,alkylamino, dialkylamino, and alkoxycarbonyl. In still anotherembodiment, the R⁸ pyridinyl substituent may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, and alkyl.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; and R⁵ is selected from the groupconsisting of —(CH₂)_(m)OR⁵⁰, —(CH₂)_(m)C(O)OR⁵⁰, and—(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, 3, 4, 5, or 6; R⁵⁰ isselected from the group consisting of hydrogen and alkyl; R⁵¹ and R⁵²are independently selected from the group consisting of hydrogen andalkyl; or R⁵¹ and R⁵² together with the nitrogen to which they areattached form a five- or six-membered ring heterocyclyl; wherein theR⁵⁰, R⁵¹ and R⁵² alkyl substituents and the R⁵¹/R⁵² heterocyclylsubstituent may be independently and optionally substituted with one ormore substituents selected from the group consisting of halogen,pyrrolidinyl, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵,—N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³is selected from the group consisting of hydrogen, alkyl, haloalkyl,hydroxyalkyl, and carboxyalkyl; R⁵⁴ and R⁵⁵ are independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl,and carboxyalkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen to whichthey are attached form a five- or six-membered ring heterocyclyl; andR⁵⁶ is selected from the group consisting of hydrogen and alkyl. Instill another embodiment, R⁵ is —(CH₂)_(m)C(O)OR⁵³; m is 0; and R⁵⁰ isselected from the group consisting of hydrogen and alkyl. In stillanother embodiment, R⁵ is —(CH₂)_(m)C(O)OR⁵³; m is 0; and R⁵⁰ ishydrogen.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of (C₃-C₇)-cycloalkyl and phenyl; wherein the R¹(C₃-C₇)-cycloalkyl and phenyl substituents may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ isselected from the group consisting of —(CH₂)_(m)OR⁵³,—(CH₂)_(m)C(O)OR⁵⁰, and —(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, 3,4, 5, or 6; R⁵⁰ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; R⁵¹ and R⁵² are independently selected from the groupconsisting of hydrogen and (C₁-C₆)-alkyl; or R⁵¹ and R⁵² together withthe nitrogen to which they are attached form a five- or six-memberedring heterocyclyl; wherein the R⁵⁰, R⁵¹ and R⁵² (C₁-C₆)-alkylsubstituents and the R⁵¹/R⁵² heterocyclyl substituent may beindependently and optionally substituted with one or more substituentsselected from the group consisting of halogen, pyrrolidinyl, —OR⁵³,—C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵, —N(R⁵⁸)C(O)R⁵³;—S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³ is selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁶⁵ areindependently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen towhich they are attached form a five- or six-membered ring heterocyclyl;and R⁵⁶ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; and R⁸ is selected from the group consisting of phenyland pyridinyl; wherein the R⁸ phenyl and pyridinyl substituents may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl. In still anotherembodiment, X is —CH₂—. In still another embodiment, X is —O—.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁸ and R⁷ are each hydrogen; R¹ is (C₃-C₇)-cycloalkyl; wherein theR¹ (C₃-C₇)-cycloalkyl substituent may be optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is selected from thegroup consisting of —(CH₂)_(m)OR⁵⁰, —(CH₂)_(m)C(O)OR⁵⁰, and—(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, 3, 4, 5, or 6; R⁵⁰ isselected from the group consisting of hydrogen and (C₁-C₆)-alkyl; R⁵¹and R⁵² are independently selected from the group consisting of hydrogenand (C₁-C₆)-alkyl; or R⁵¹ and R⁵² together with the nitrogen to whichthey are attached form a five- or six-membered ring heterocyclyl;wherein the R⁵⁰. R⁵¹ and R⁵² (C₁-C₆)-alkyl substituents and the R⁵¹/R⁵²heterocyclyl substituent may be independently and optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, pyrrolidinyl, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1or 2; R⁵³ is selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen towhich they are attached form a five- or six-membered ring heterocyclyl;and R⁵⁶ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; and R⁸ is selected from the group consisting of phenyland pyridinyl; wherein the R⁸ phenyl and pyridinyl substituents may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₅)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl. In still anotherembodiment, X is —CH₂—. In still another embodiment, X is —O—. In stillanother embodiment, R¹ is selected from the group consisting ofcyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. In still anotherembodiment, R¹ is cyclopentyl.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is phenyl; wherein the R¹ phenylsubstituent may be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen,(C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is selected from the groupconsisting of —(CH₂)_(m)OR⁵⁰, —(CH₂)_(m)C(O)OR⁵⁰, and—(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, 3, 4, 5, or 6; R⁵⁰ isselected from the group consisting of hydrogen and (C₁-C₆)-alkyl; R⁵¹and R⁵² are independently selected from the group consisting of hydrogenand (C₁-C₆)-alkyl; or R⁵¹ and R⁵² together with the nitrogen to whichthey are attached form a five- or six-membered ring heterocyclyl;wherein the R⁵⁰, R⁵¹ and R⁵² (C₁-C₆)-alkyl substituents and the R⁵¹/R⁵²heterocyclyl substituent may be independently and optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, pyrrolidinyl, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1or 2; R⁵³ is selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-(|₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; or R⁵⁴ and R⁵⁵together with the nitrogen to which they are attached form a five- orsix-membered ring heterocyclyl; and R⁵⁸ is selected from the groupconsisting of hydrogen and (C₁-C₆)alkyl; and R⁸ is selected from thegroup consisting of phenyl and pyridinyl; wherein the R⁸ phenyl andpyridinyl substituents may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, carboxy, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,cyano-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl.In still another embodiment, the R¹ phenyl substituent may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, (C₁-C₆)-alkyl and halo-(C₁-C₆)-alkyl.In still another embodiment, the R¹ phenyl substituent is substitutedwith one or more halogen substituents. In still another embodiment, theR¹ phenyl substituent may be optionally substituted with one or moresubstituents independently selected from the group consisting of chloroand fluoro. In still another embodiment, the R¹ phenyl substituent issubstituted with one or more fluoro.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of (C₃-C₇)-cycloalkyl and phenyl; wherein the R¹(C₃-C₇)-cycloalkyl and phenyl substituents may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ isselected from the group consisting of —(CH₂)_(m)OR⁵⁰,—(CH₂)_(m)C(O)OR⁵³, and —(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, 3,4, 5, or 6; R⁵⁰ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; R⁵¹ and R⁵² are independently selected from the groupconsisting of hydrogen and (C₁-C₆)-alkyl; or R⁵¹ and R⁵² together withthe nitrogen to which they are attached form a five- or six-memberedring heterocyclyl; wherein the R⁵⁰, R⁵¹ and R⁵² (C₁-C₆)-alkylsubstituents and the R⁵¹/R⁵² heterocyclyl substituent may beindependently and optionally substituted with one or more substituentsselected from the group consisting of halogen, pyrrolidinyl, —OR⁵³,—C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³;—S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³ is selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ areindependently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen towhich they are attached form a five- or six-membered ring heterocyclyl;and R⁵⁶ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; and R⁸ is phenyl; wherein the R⁸ phenyl substituent issubstituted with one or more cyano substituents and, optionally, may befurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, hydroxy, carboxy, (C₁-C₆)-alkyl,halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl,carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halo-(C₁-C₆)-alkoxy,cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino,and (C₁-C₆)-alkoxycarbonyl. In still another embodiment, the R⁸ phenylsubstituent is substituted with one or more cyano substituents and,optionally, may be further substituted with one or more substituentsindependently selected from the group consisting of halogen,(C₁-C₆)-alkyl and (C₁-C₆)-alkoxy. In still another embodiment, the R⁸phenyl substituent is substituted with one or more cyano substituentsand, optionally, may be further substituted with one or more halogensubstituents. In still another embodiment, the R⁸ phenyl substituent issubstituted with one or more cyano substituents and, optionally, may befurther substituted with one or more substituents independently selectedfrom the group consisting of chloro and fluoro. In still anotherembodiment, the R⁸ phenyl substituent is substituted with one or morecyano substituents and optionally, may be further substituted with oneor more chloro. In still another embodiment, the R⁸ phenyl substituentis substituted with one or more cyano substituents and, optionally, maybe further substituted with one or more (C₁-C₆)-alkyl substituents. Instill another embodiment, the R⁸ phenyl substituent is substituted withone or more cyano substituents and, optionally, may be furthersubstituted with one or more (C₁-C₄).alkyl substituents. In stillanother embodiment, R⁸ phenyl substituent is substituted with one ormore cyano substituents and, optionally, may be further substituted withone or more methyl substituents.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of (C₃-C₇)-cycloalkyl and phenyl; wherein the R¹(C₃-C₇)-cycloalkyl and phenyl substituents may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is—(CH₂)_(m)C(O)OR⁵⁰; wherein m is 0, 1, 2, 3, 4, 5, or 6; R⁵⁰ is selectedfrom the group consisting of hydrogen and (C₁-C₆)-alkyl; wherein the R⁵⁰(C₁-C₆)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵,—N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³is selected from the group consisting of hydrogen, (C₁-C₆)-alkyl,halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl;R⁵⁴ and R⁵⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen towhich they are attached form a five- or six-membered ring heterocyclyl;and R⁵⁶ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; and R⁸ is selected from the group consisting of phenyland pyridinyl; wherein the R⁸ phenyl and pyridinyl substituents may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl. In still anotherembodiment, m is 0. In still another embodiment. R⁵⁰ is hydrogen. Instill another embodiment, m is 0, and R⁵⁰ is hydrogen.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of (C₃-C₇)-cycloalkyl and phenyl; wherein the R¹(C₃-C₇)-cycloalkyl and phenyl substituents may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is—(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, 3, 4, 5, or 6; R⁵¹ and R⁵²are independently selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; or R⁵¹ and R⁵² together with the nitrogen to which theyare attached form a five- or six-membered ring heterocyclyl; wherein theR⁵¹ and R⁵² (C₁-C₆)-alkyl substituents and the R⁵¹/R⁵² heterocyclylsubstituent may be independently and optionally substituted with one ormore substituents selected from the group consisting of halogen,pyrrolidinyl, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵,—N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³is selected from the group consisting of hydrogen, (C₁-C₆)-alkyl,halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl;R⁵⁴ and R⁵⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen towhich they are attached form a five- or six-membered ring heterocyclyl;and R⁵⁶ is selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; and R⁸ is selected from the group consisting of phenyland pyridinyl; wherein the R⁸ phenyl and pyridinyl substituents may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl. In still anotherembodiment, m is 0. In still another embodiment, R⁵⁰ is hydrogen. Instill another embodiment, m is 0; and R⁵¹ and R⁵² are independentlyselected from the group consisting of hydrogen and (C₁-C₆)-alkyl. Instill another embodiment, m is 0; and R⁵¹ and R⁵² are independentlyselected from the group consisting of hydrogen and (C₁-C₆)-alkyl;wherein the R⁵¹ and R⁵² (C₁-C₆)-alkyl substituents may be independentlyand optionally substituted with one or more substituents selected fromthe group consisting of —OR⁵³ and —S(O)_(p)R⁵³; p is 0, 1 or 2; and R⁵³is selected from the group consisting of hydrogen and (C₁-C₆)-alkyl.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of cyclopentyl and phenyl; wherein the R¹ cyclopentyl andphenyl substituents may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is selected from thegroup consisting of —(CH₂)_(m)OR⁵⁰, —(CH₂)_(m)C(O)OR⁵⁶, and—(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, or 3; R⁵⁰ is selected fromthe group consisting of hydrogen and (C₁-C₆)-alkyl; R⁵¹ and R⁵² areindependently selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; wherein the R⁵⁰, R⁵¹ and R⁵² (C₁-C₆)-alkyl substituentsmay be independently and optionally substituted with one or moresubstituents selected from the group consisting of halogen, —OR⁵³,—C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³;—S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³ is selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ areindependently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; and R⁵⁶ is selected from the group consisting ofhydrogen and (C₁-C₆)-alkyl; and R⁸ is selected from the group consistingof phenyl and pyridinyl; wherein the R⁸ phenyl and pyridinylsubstituents may be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, carboxy, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,cyano-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl.In still another embodiment, X is —CH₂—. In still another embodiment, Xis —O—.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of cyclopentyl and phenyl; wherein the R¹ cyclopentyl andphenyl substituents may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is selected from thegroup consisting of —(CH₂)_(m)OR⁵⁶, —(CH₂)_(m)C(O)OR⁵⁶, and—(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein m is 0, 1, 2, or 3; R⁵⁰ is selected fromthe group consisting of hydrogen and (C₁-C₆)-alkyl; R⁵¹ and R⁵² areindependently selected from the group consisting of hydrogen and(C₁-C₆)-alkyl; wherein the R⁵⁵, R⁵¹ and R⁵² (C₁-C₆)-alkyl substituentsmay be independently and optionally substituted with one or moresubstituents selected from the group consisting of halogen, —OR⁵³,—C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³;—S(O)_(m)R⁵³, and —S(O)_(m)NR⁵⁴R⁵⁵; p is 0, 1 or 2; R⁵³ is selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ areindependently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; and R⁵⁶ is selected from the group consisting ofhydrogen and (C₁-C₆)-alkyl; and R⁸ is selected from the group consistingof phenyl and pyridinyl; wherein the R⁸ phenyl and pyridinylsubstituents may be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, carboxy, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,cyano-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl.In still another embodiment, X is —CH₂—. In still another embodiment, Xis —O—. In still another embodiment. R¹ is cyclopentyl; wherein the R¹cyclopentyl substituent may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, (C₁-C₄)-alkyl, and halo-(C₁-C₄)-alkyl. In still anotherembodiment, R¹ is phenyl; wherein the R¹ phenyl substituent may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, (C₁-C₄)-alkyl, andhalo-(C₁-C₄)-alkyl. In still another embodiment. R⁵ is—(CH₂)_(m)C(O)OR⁵⁶; m is 0; and R⁵⁰ is selected from the groupconsisting of hydrogen and alkyl. In still another embodiment. R⁵ is—(CH₂)_(m)C(O)OR⁵⁰; m is 0; and R⁵⁰ is hydrogen. In still anotherembodiment, R⁸ is phenyl; wherein the R⁸ phenyl substituent may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl. In still anotherembodiment. R⁸ is pyridinyl; wherein the R⁸ pyridinyl substituent may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, and —(C₁-C₆)-alkoxycarbonyl.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of cyclopentyl and phenyl; wherein the R¹ cyclopentyl andphenyl substituents may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, (C₁-C₆)-alkyl, and halo-(C₁-C₆)-alkyl; R⁵ is—(CH₂)_(m)C(O)OR⁵⁰; wherein m is 0, 1, 2, or 3; R⁵⁰ is selected from thegroup consisting of hydrogen and (C₁-C₆)-alkyl; wherein the R⁵⁰(C₁-C₆)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1or 2; R⁵³ is selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; and R⁵⁶ is selectedfrom the group consisting of hydrogen and (C₁-C₆)-alkyl; and R⁸ isselected from the group consisting of phenyl and pyridinyl; wherein theR⁸ phenyl and pyridinyl substituents may be optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, carboxy, (C₁-C₆)-alkyl,halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl,carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halo-(C₁-C₆)-alkoxy,cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino, anddi-(C₁-C₆)-alkylamino. In still another embodiment, X is —CH₂—. In stillanother embodiment, X is —O—. In still another embodiment, R¹ iscyclopentyl; wherein the R¹ cyclopentyl substituent may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, (C₁-C₄)-alkyl, and halo-(C₁-C₄)-alkyl.In still another embodiment, R¹ is phenyl; wherein the R¹ phenylsubstituent may be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen,(C₁-C₄)-alkyl, and halo-(C₁-C₄)-alkyl. In still another embodiment, R⁵is —(CH₂)_(m)C(O)OR⁵⁰; m is 0; and R⁵⁰ is selected from the groupconsisting of hydrogen and (C₁-C₆)-alkyl. In still another embodiment,R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; m is 0; and R⁵⁰ is hydrogen. In still anotherembodiment, R⁸ is phenyl; wherein the R⁸ phenyl substituent may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,halo-(C₁-C₆)-alkoxy, cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino anddi-(C₁-C₆)-alkylamino. In still another embodiment, R⁸ is pyridinyl;wherein the R⁸ pyridinyl substituent may be optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, carboxy, (C₁-C₆)-alkyl,halo-(C₁-C₆)-alkyl, cyano-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl,carboxy-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halo-(C₁-C₆)-alkoxy,cyano-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylamino anddi-(C₁-C₆)-alkylamino.

In another embodiment of the compounds of Formula I, R², R^(3A), R^(3B),R⁴, R⁶ and R⁷ are each hydrogen; R¹ is selected from the groupconsisting of cyclopentyl and phenyl; wherein the R¹ cyclopentyl andphenyl substituents may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, (C₁-C₄)-alkyl, and halo-(C₁-C₄)-alkyl; R⁵ is—(CH₂)_(m)C(O)OR⁵⁰: wherein m is 0, 1, or 2; R⁵⁰ is selected from thegroup consisting of hydrogen and (C₁-C₄)-alkyl; wherein the R⁵⁰(C₁-C₄)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, and —C(O)OR⁵³; R⁵³ is selectedfrom the group consisting of hydrogen and (C₁-C₄)-alkyl; and R⁸ isselected from the group consisting of phenyl and pyridinyl; wherein theR⁸ phenyl and pyridinyl substituents may be optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, carboxy, (C₁-C₄)-alkyl,halo-(C₁-C₄)-alkyl, cyano-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, andcarboxy-(C₁-C₄)-alkyl. In still another embodiment, X is —CH₂—. In stillanother embodiment, X is —O—. In still another embodiment, R¹ iscyclopentyl; wherein the R¹ cyclopentyl substituent may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, (C₁-C₄)-alkyl, and halo-(C₁-C₄)-alkyl.In still another embodiment, R¹ is phenyl; wherein the R¹ phenylsubstituent may be optionally substituted with one or more substituentsindependently selected from the group consisting of halogen,(C₁-C₄)-alkyl, and halo-(C₁-C₄)-alkyl. In still another embodiment, R⁵is —(CH₂)_(m)C(O)OR⁵⁰; m is 0; and R⁵⁰ is selected from the groupconsisting of hydrogen and (C₁-C₄)-alkyl. In still another embodiment,R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; m is 0; and R⁵⁰ is hydrogen. In still anotherembodiment, R⁸ is phenyl; wherein the R⁸ phenyl substituent may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₄)-alkyl, halo-(C₁-C₄)-alkyl, cyano-(C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl and carboxy-(C₁-C₄)-alkyl. In still anotherembodiment, R⁸ is pyridinyl; wherein the R⁸ pyridinyl substituent may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,(C₁-C₄)-alkyl, halo-(C₁-C₄)-alkyl, cyano-(C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl and carboxy-(C₁-C₄)-alkyl.

The present invention is also directed to a subclass of compounds(including pharmaceutically acceptable salts and tautomers of thecompounds), wherein the compounds have the structure of Formula II:

wherein:

X is selected from the group consisting of —CH₂— and —O—;

Z is selected from the group consisting of —C(R⁸¹)— and —N—;

R¹ is selected from the group consisting of cyclopentyl and phenyl;wherein the R¹ cyclopentyl and phenyl substituents may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of chloro, fluoro, methyl, ethyl, propyl,chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl,difluoromethyl and trifluoromethyl;

R² is selected from the group consisting of hydrogen or (C₁-C₄)-alkyl;

R⁵ is selected from the group consisting of —(CH₂)_(m)OR⁵⁰,—(CH₂)_(m)C(O)OR⁵⁰, and —(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein:

m is 0, 1, 2, or 3;

R⁵⁰ is selected from the group consisting of hydrogen and (C₁-C₆)-alkyl;

R⁵¹ and R⁵² are independently selected from the group consisting ofhydrogen and (C₁-C₆)-alkyl; wherein the R⁵³, R⁵¹ and R⁵² (C₁-C₆)-alkylsubstituents may be independently and optionally substituted with one ormore substituents selected from the group consisting of halogen, —OR⁵³,—C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³;—S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵;

p is 0, 1 or 2;

R⁵³ is selected from the group consisting of hydrogen, (C₁-C₆)-alkyl,halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl;

R⁵⁴ and R⁵⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; and

R⁸¹, R⁸², R⁸³, R⁸⁴, and R⁸⁵ are independently selected from the groupconsisting of hydrogen, chloro, fluoro, cyano, hydroxy, carboxy, methyl,ethyl, trichloromethyl, trifluoromethyl, cyanomethyl, hydroxymethyl,carboxymethyl, methoxy, amino, methylamino, and dimethylamino.

In one embodiment of the compounds of Formula II, R² is methyl.

In another embodiment of the compounds of Formula II, R² is hydrogen.

In another embodiment of the compounds of Formula II, R² is hydrogen; R⁵is —(CH₂)_(m)C(O)OR⁵⁰; wherein m is 0, 1, 2, or 3; R⁵⁰ is selected fromthe group consisting of hydrogen and (C₁-C₆)-alkyl; wherein the R⁵⁰(C₁-C₆)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁶)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1or 2; R⁵³ is selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; and R⁵⁴ and R⁵⁵ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl.

In another embodiment of the compounds of Formula II, R² is hydrogen; R⁵is —(CH₂)_(m)C(O)OR⁵⁰; wherein m is 0, 1, or 2; R⁵⁰ is selected from thegroup consisting of hydrogen and (C₁-C₄)-alkyl; wherein the R⁵⁰(C₁-C₄)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, and —C(O)OR⁵³; and R⁵³ isselected from the group consisting of hydrogen and (C₁-C₄)-alkyl.

In another embodiment of the compounds of Formula II, R² is hydrogen; Zis selected from the group consisting of —C(R⁸¹)— and —N—; R¹ isselected from the group consisting of cyclopentyl and phenyl; whereinthe R¹ cyclopentyl and phenyl substituents may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of chloro, fluoro, methyl, and trifluoromethyl; R⁵ is—(CH₂)_(m)C(O)OR⁵⁰; wherein m is 0, 1, or 2; R⁵⁰ is selected from thegroup consisting of hydrogen and (C₁-C₄)-alkyl; wherein the R⁵⁰(C₁-C₄)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, and —C(O)OR⁵³; and R⁵³ isselected from the group consisting of hydrogen and (C₁-C₄)-alkyl; andR⁸¹, R⁸², R⁸³, R⁸⁴, and R⁸⁵ are independently selected from the groupconsisting of hydrogen, chloro, fluoro, cyano, hydroxy, carboxy, methyl,ethyl, cyanomethyl, hydroxymethyl, carboxymethyl, methoxy, amino,methylamino, and dimethylamino.

In another embodiment of the compounds of Formula II, R² is hydrogen; Zis selected from the group consisting of —C(R⁸¹)— and —N—; R¹ isselected from the group consisting of cyclopentyl and phenyl; whereinthe R¹ cyclopentyl and phenyl substituents may be optionally substitutedwith fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein m is 0; R⁵⁰ is selectedfrom the group consisting of hydrogen and (C₁-C₄)-alkyl; and R⁸¹ and R⁸⁵are each hydrogen; and R⁸², R⁸³, and R⁸⁴ are independently selected fromthe group consisting of chloro, cyano, and methyl.

In another embodiment of the compounds of Formula II, R² is hydrogen; Xis —CH₂—; Z is —C(R⁸¹)—; R¹ is selected from the group consisting ofcyclopentyl and phenyl; wherein the R¹ phenyl substituent may beoptionally substituted with fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein mis 0; R⁵⁰ is hydrogen; R⁸¹, R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² andR⁸³ are independently selected from the group consisting of chloro,cyano, and methyl. In still another embodiment, R⁸² is selected from thegroup consisting of chloro and methyl; and R⁸³ is cyano. In stillanother embodiment, R⁸² is chloro and R⁸³ is cyano. In still anotherembodiment, R¹ is cyclopentyl. In still another embodiment, R¹ isphenyl; wherein the R¹ phenyl substituent may be optionally substitutedwith fluoro. In still another embodiment, R¹ is phenyl; wherein the R¹phenyl substituent may be optionally substituted with fluoro at the paraposition.

In another embodiment of the compounds of Formula II, R² is hydrogen; Xis —O—; Z is —C(R⁸¹)—; R¹ is selected from the group consisting ofcyclopentyl and phenyl; wherein the R¹ phenyl substituent may beoptionally substituted with fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein mis 0; R⁵⁰ is hydrogen; R⁸¹, R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² andR⁸³ are independently selected from the group consisting of chloro,cyano, and methyl. In still another embodiment, R⁸² is selected from thegroup consisting of chloro and methyl; and R⁸³ is cyano. In stillanother embodiment, R⁸² is chloro and R⁸³ is cyano. In still anotherembodiment, R¹ is cyclopentyl. In still another embodiment, R¹ isphenyl; wherein the R¹ phenyl substituent may be optionally substitutedwith fluoro. In still another embodiment, R¹ is phenyl; wherein the R¹phenyl substituent may be optionally substituted with fluoro at the paraposition.

In another embodiment of the compounds of Formula II, R² is hydrogen; Xis —CH₂—; Z is —N—; R¹ is selected from the group consisting ofcyclopentyl and phenyl; wherein the R¹ phenyl substituent may beoptionally substituted with fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein mis 0; R⁵⁰ is hydrogen; R⁸¹, R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² andR⁸³ are independently selected from the group consisting of chloro,cyano, and methyl. In still another embodiment, R⁸² is selected from thegroup consisting of chloro and methyl; and R⁸³ is cyano. In stillanother embodiment, R⁸² is chloro and R⁸³ is cyano. In still anotherembodiment, R¹ is cyclopentyl. In still another embodiment, R¹ isphenyl; wherein the R¹ phenyl substituent may be optionally substitutedwith fluoro. In still another embodiment, R¹ is phenyl; wherein the R¹phenyl substituent may be optionally substituted with fluoro at the paraposition.

In another embodiment of the compounds of Formula II, R² is hydrogen; Xis —O—; Z is —N—; R¹ is selected from the group consisting ofcyclopentyl and phenyl; wherein the R¹ phenyl substituent may beoptionally substituted with fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein inis 0; R⁵⁰ is hydrogen; R⁸¹, R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² andR⁸³ are independently selected from the group consisting of chloro,cyano, and methyl. In still another embodiment, R⁸² is selected from thegroup consisting of chloro and methyl; and R⁸³ is cyano. In stillanother embodiment, R⁸² is chloro and R⁸³ is cyano. In still anotherembodiment, R¹ is cyclopentyl. In still another embodiment, R¹ isphenyl; wherein the R¹ phenyl substituent may be optionally substitutedwith fluoro. In still another embodiment, R¹ is phenyl; wherein the R¹phenyl substituent may be optionally substituted with fluoro at the paraposition.

In another embodiment, the compounds of Formula I are selected from thegroup consisting of:

-   2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile;-   3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile;-   2-chloro-4-(3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile;-   2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;    and-   2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.

In another embodiment, the compounds of Formula I are selected from thegroup consisting of:

-   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(5-cyano-6-methylpyridin-2-yl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   N-(−2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide;

In another embodiment, the compounds of Formula I are selected from thegroup consisting of:

-   methyl    2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate;-   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3a-methyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;-   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-hydroxyethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;    and-   2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic    acid.

In another embodiment, the compounds of Formula I are selected from thegroup consisting of:

-   2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid; and-   2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid.

In another embodiment, the compounds of Formula I are selected from thegroup consisting of:

-   2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic    acid;-   2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;    and-   2-(3-chloro-4-cyanophenyl)-N-[2-(methylsulfonyl)ethyl]-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.

In another embodiment, the compounds of Formula I are selected from thegroup consisting of:

-   2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic    acid;-   2-[4-cyano-3-(trifluoromethyl(phenyl]-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic    acid;-   2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic    acid; and-   2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic    acid.

C. ISOMERS

The compounds of the present invention can be present as stereoisomers,such as enantiomers and diastereomers. For example, the compounds(including the compounds of Formulae I and II) generally comprise two ormore asymmetric carbon atoms and can be present in the form of one ormore stereoisomers (e.g., individual enantiomers, diastereomers, andmixtures thereof). More specifically, the compounds of the presentinvention can be present as the 3R,3aR stereoisomer, the 3S,3aSstereoisomer, the 3S,3aR stereoisomer, the 3R,3aS stereoisomer, or amixture of two or more of these stereoisomers.

In one embodiment, the compound of Formulae I or II has the 3R,3aRconfiguration.

In another embodiment, the compound of Formulae I or II has the 3S,3aSconfiguration.

In another embodiment, the compound of Formulae I or II has the 3S,3aRconfiguration.

In another embodiment, the compound of Formulae I or II has the 3R,3aSconfiguration.

In another embodiment, the compound of Formulae I or II is present as amixture of two or more stereoisomers selected from the group consistingof the 3R,3aR stereoisomer, the 3S,3aS stereoisomer, the 3S,3aRstereoisomer, and the 3R,3aS stereoisomer.

In addition, when a compound of the present invention contains analkenyl group or moiety, geometric isomers may arise

D. TAUTOMERIC FORMS

The present invention comprises the tautomeric forms of compounds ofFormulae I and II. Where structural isomers are interconvertible via alow energy barrier, tautomeric isomerism (‘tautomerism’) can occur. Thiscan take the form of proton tautomerism in compounds of formula Icontaining, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism. The various ratios of the tautomers in solid and liquid formare dependent on the various substituents on the molecule as well as theparticular crystallization technique used to isolate a compound.

E. SALTS

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), an exemplary salt ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of Formulae I or IIwith an acid whose anion, or a base whose cation, is generallyconsidered suitable for human consumption. Pharmaceutically acceptablesalts are particularly useful as products of the methods of the presentinvention because of their greater aqueous solubility relative to theparent compound. For use in medicine, the salts of the compounds of thisinvention are non-toxic “pharmaceutically acceptable salts.” Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, e.g. hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids, e.g. acetic,benzenesulfonic, benzoic, citric, malic, ethanesulfonic, fumaric,gluconic, glycolic, isothionic, lactic, lactobionic, maleic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids.

Suitable organic acids generally include, for example, aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclylic, carboxylic, andsulfonic classes of organic acids. Specific examples of suitable organicacids include acetate, trifluoroacetate, formate, propionate, succinate,glycolate, gluconate, digluconate, lactate, malate, tartaric acid,citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, p-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, butyrate, camphorate,camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate,picrate, pivalate, thiocyanate, tosylate, and undecanoate.

In another embodiment, examples of suitable addition salts formedinclude the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsyate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts. In anotherembodiment, representative salts include benzenesulfonate, hydrobromideand hydrochloride.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others. In one embodiment, hemisaltsof acids and bases may also be formed, for example, hemisulphate andhemicalcium salts.

F. PRODRUGS

Also within the scope of the present invention are so-called “prodrugs”of the compounds of Formulae I and II. Thus, certain derivatives ofcompounds of any of Formulae I or II which may have little or nopharmacological activity themselves can, when administered into or ontothe body, be converted into compounds of any of Formulae I or II havingthe desired activity, for example, by hydrolytic cleavage. Suchderivatives are referred to as “prodrugs.”

Further information on the use of prodrugs may be found in “Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and WStella) and “Bioreversible Carriers in Drug Design,” Pergamon Press,1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs inaccordance with the invention can, for example, be produced by replacingappropriate functionalities present in the compounds of any of FormulaeI or II with certain moieties known to those skilled in the art as“pro-moieties” as described, for example, in “Design of Prodrugs” byhours Bundgaard (Elseview, 1985).

G. METHODS OF TREATMENT

The present invention further comprises methods for treating a conditionin a subject having or susceptible to having such a condition, byadministering to the subject a therapeutically-effective amount of oneor more compounds of Formulae I and II as described above. In oneembodiment, the treatment is preventative treatment. In anotherembodiment, the treatment is palliative treatment. In anotherembodiment, the treatment is restorative treatment.

1. Conditions

The conditions that can be treated in accordance with the presentinvention include, but are not limited to, cardiovascular conditions,renal conditions, liver conditions, vascular conditions, inflammatoryconditions, pain, retinopathy, neuropathy (such as peripheralneuropathy), insulinopathy, edema, endothelial dysfunction, baroreceptordysfunction and the like.

Cardiovascular conditions include, but are not limited to, hypertension,heart failure (such as congestive heart failure), diastolic dysfunction(such as left ventricular diastolic dysfunction, diastolic heartfailure, and impaired diastolic filling), systolic dysfunction (such assystolic heart failure), arrhythmia, ischemia, hypertrophiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, fibrinoid necrosis of coronary arteries, stroke,and the like.

Renal conditions include, but are not limited to, glomerulosclerosis,end-stage renal disease, diabetic nephropathy, reduced renal blood flow,increased glomerular filtration fraction, proteinuria, decreasedglomerular filtration rate, decreased creatinine clearance,microalbuminuria, renal arteriopathy, ischemic lesions, thromboticlesions, global fibrinoid necrosis, focal thrombosis of glomerularcapillaries, swelling and proliferation of intracapillary (endothelialand mesangial) and/or extracapillary cells (crescents), expansion ofreticulated mesangial matrix with or without significanthypercellularity, malignant nephrosclerosis (such as ischemicretraction, thrombonecrosis of capillary tufts, arteriolar fibrinoidnecrosis, and thrombotic microangiopathic lesions affecting glomeruliand microvessels), and the like.

Liver conditions include, but are not limited to, liver cirrhosis, liverascites, hepatic congestion, and the like.

Vascular conditions include, but are not limited to, thrombotic vasculardisease (such as mural fibrinoid necrosis, extravasation andfragmentation of red blood cells, and luminal and/or mural thrombosis),proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction, and the like.

Inflammatory conditions include, but are not limited to, arthritis (forexample, osteoarthritis), inflammatory airways diseases (for example,chronic obstructive pulmonary disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (forexample, arthralgia), and the like.

Edema includes, but is not limited to, peripheral tissue edema, hepaticcongestion, splenic congestion, liver ascites, respiratory or lungcongestion, and the like.

Insulinopathies include, but are not limited to, insulin resistance,Type I diabetes mellitus, Type II diabetes mellitus, glucosesensitivity, pre-diabetic state, syndrome X, and the like.

In one embodiment, the condition is selected from the group consistingof cardiovascular conditions, renal conditions, and liver conditions.

In another embodiment, the condition is a cardiovascular condition.

In another embodiment, the condition is a cardiovascular conditionselected from the group consisting of hypertension, heart failure(particularly heart failure post myocardial infarction), leftventricular hypertrophy, and stroke.

In another embodiment, the condition is hypertension.

In another embodiment, the condition is heart failure.

In another embodiment, the condition is left ventricular hypertrophy.

In another embodiment, the condition is stroke.

In another embodiment, the condition is a renal condition.

In another embodiment, the condition is nephropathy.

In another embodiment, the condition is Type II diabetes mellitus.

2. Subjects

Suitable subjects to be treated according to the present inventioninclude mammalian subjects. Mammals according to the present inventioninclude, but are not limited to, canine, feline, bovine, caprine,equine, ovine, porcine, rodents, lagomorphs, primates, and the like, andencompass mammals in utero. In one embodiment, humans are suitablesubjects. Human subjects may be of either gender and at any stage ofdevelopment.

3. Administration and Dosing

The compounds of the present invention are generally administered in atherapeutically effective amount. In one embodiment, the compounds ofthe present invention are administered in a mineralocorticoid receptorantagonizing amount.

The compounds of the present invention can be administered by anysuitable route in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended.Therapeutically effective doses of the compounds of the presentinvention required to prevent or arrest the progress of, or to treat themedical condition, are readily ascertained by one of ordinary skill inthe art using preclinical and clinical approaches familiar to themedicinal arts.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary based onthe specific situation. Dosage levels from about 0.001 mg to about 100mg of the compound of the present invention per kilogram of body weightper day are useful in the treatment of the above-indicated conditions.In one embodiment, the total daily dose of the compound of the presentinvention (administered in single or divided doses) is typically fromabout 0.001 mg/kg to about 20 mg/kg (i.e., mg compound/kg body weight).In another embodiment, the total daily dose of the compound of thepresent invention is from about 0.005 mg/kg to about 10 mg/kg. Inanother embodiment, the total daily dose is from about 0.005 mg/kg toabout 5 mg/kg. In another embodiment, the total daily dose is from about0.01 mg/kg to about 1 mg/kg. In another embodiment, the total daily doseis from about 0.8 mg/kg to about 15 mg/kg. In another embodiment, thetotal daily dose is from about 0.2 mg/kg to about 4 mg/kg. These dosagesare based on an average human subject having a weight of about 65 kg toabout 75 kg. A physician will readily be able to determine doses forsubjects whose weight falls outside of this range, such as infants. Theadministration of the compound of the present invention can be repeateda plurality of times in a day (typically no greater than 4 times) toachieve the desired daily dose.

For convenience the compounds of the present invention can beadministered in a unit dosage form. If desired, multiple doses per dayof the unit dosage form can be used to increase the total daily dose.The unit dosage form, for example, may be a tablet or capsule containingabout 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250 or 500mg of the compound of the present invention. In one embodiment, the unitdosage form contains from about 0.01 mg to about 500 mg of the compoundof the present invention. In another embodiment, the unit dosage formcontains from about 0.05 mg to about 250 mg of the compound of thepresent invention. In another embodiment, the unit dosage form containsfrom about 0.1 mg to about 200 mg of the compound of the presentinvention. In another embodiment, the unit dosage form contains fromabout 0.5 mg to about 150 mg of the compound of the present invention.

H. USE IN THE PREPARATION OF A MEDICAMENT

The present invention further comprises use of a compound of Formulae Ior II for use as a medicament (such as a unit dosage tablet or unitdosage capsule).

In another embodiment, the present invention comprises the use of acompound of Formulae I or II for the manufacture of a medicament (suchas a unit dosage tablet or unit dosage capsule) to treat one or more ofthe conditions previously identified in the above sections discussingmethods of treatment. In one embodiment, the condition is hypertension.In another embodiment the condition is heart failure.

I. PHARMACEUTICAL COMPOSITIONS

For the treatment of the conditions referred to above, the compounds ofFormulae I or II can be administered as the compound per se.Alternatively, pharmaceutically acceptable salts are suitable formedical applications because of their greater aqueous solubilityrelative to the parent compound. In addition, the compounds of thepresent invention can be administered in the form of a pharmaceuticalcomposition comprising a compound of Formula I or II, or apharmaceutically acceptable salt thereof, and apharmaceutically-acceptable carrier. The carrier can be a solid, aliquid, or both, and may be formulated with the compound as a unit-dosecomposition, for example, a tablet, which can contain from 0.05% to 95%by weight of the active compounds. Other pharmacologically activesubstances can also be present.

The active compounds of the present invention may be administered by anysuitable route, wherein one exemplary form of a pharmaceuticalcomposition is adapted to such a route, and in a dose effective for thetreatment intended. The active compounds and compositions, for example,may be administered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of Formulae I or IIare ordinarily combined with one or more adjuvants. In the case ofcapsules, tablets, and pills, the dosage forms also may comprisebuffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneally, intramuscularinjections, intrasternal injections, and infusion. Injectablepreparations (e.g., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting agents, and/or suspending agents.

In another embodiment, the present invention comprises a topical doseform. In still another embodiment, the present invention comprises adose form for intranasal administration or administration by inhalation.In still another embodiment, the present invention comprises a rectaldose form.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

J. COMBINATIONS AND COMBINATION THERAPY

The compounds of the present invention can be used, alone or incombination with other pharmaceutically active compounds, to treatconditions such as those previously described above. The compound(s) ofthe present invention and other pharmaceutically active compound(s) canbe administered simultaneously (either in the same dosage form or inseparate dosage forms) or sequentially. Accordingly, in one embodiment,the present invention comprises methods for treating a condition byadministering to the subject a therapeutically-effective amount of oneor more compounds of Formulae I or II and one or more additionalpharmaceutically active compounds. In another embodiment, the presentinvention comprises a pharmaceutical composition comprising one or morecompounds of Formulae I or II, one or more additional pharmaceuticallyactive compounds, and a pharmaceutically acceptable carrier.

In one embodiment, one or more compounds of Formulae I or II may beco-administered with one or more diuretics. Examples of suitablediuretics include (a) loop diuretics such as furosemide (such asLASIX™), torsemide (such as DEMADEX™), bemetanide (such as BUMEX™), andethacrynic acid (such as EDECRIN™); (b) thiazide-type diuretics such aschlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™),hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), benzthiazide,hydroflumethiazide (such as SALURON™), bendroflumethiazide,methychlorthiazide, polythiazide, trichlormethiazide, and indapamide(such as LOZOL™); (c) phthalimidine-type diuretics such aschlorthalidone (such as HYGROTON™), and metolazone (such as ZAROXOLYN™);(d) quinazoline-type diuretics such as quinethazone; and (e)potassium-sparing diuretics such as triamterene (such as DYRENIUM™), andamiloride (such as MIDAMOR™ or MODURETIC™).

In another embodiment, one or more compounds of Formulae I or II may beco-administered with a loop diuretic. In still another embodiment, theloop diuretic is selected from furosemide and torsemide. In stillanother embodiment, one or more compounds of Formulae I or II may beco-administered with furosemide. In still another embodiment, one ormore compounds of Formulae I or II may be co-administered withtorsemide.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with a thiazide-type diuretic. In still anotherembodiment, the thiazide-type diuretic is selected from the groupconsisting of chlorothiazide and hydrochlorothiazide. In still anotherembodiment, one or more compounds of Formulae I or II may beco-administered with chlorothiazide. In still another embodiment, one ormore compounds of Formulae I or II may be co-administered withhydrochlorothiazide.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with a phthalimidine-type diuretic. In still anotherembodiment, the phthalimidine-type diuretic is chlorthalidone.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more angiotensin converting enzymeinhibitors. Examples of suitable angiotensin converting enzymeinhibitors include quinapril (such as ACCUPRIL™), perindopril (such asACEON™), captopril (such as CAPOTEN™), enalapril (such as VASOTEC™),ENALAPRILAT™, ramipril (such as ALTACE™) cilazapril, delapril,fosenopril (such as MONOPRIL™), zofenopril, indolapril, benazepril (suchas LOTENSIN™), lisinopril (such as PRINIVIL™ and ZESTRIL™), spirapril,trandolapril (such as MAVIK™) perindep, pentopril, moexipril (such asUNIVASC™)'fasidotril, S-allymercaptocaptopril, and pivopril.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more angiotensin II receptor blockers.Examples of suitable angiotensin II receptor blockers includecandesartan (such as ATACAND™), eprosartan (such as TEVETEN™),irbesartan (such as AVEPRO™), losartan (such as COZAAR™), olmesartan,olmesartan medoxomil (such as BENICAR™), tasosartan, telmisartan (suchas MICARDIS™), valsartan (such as DIOVAN™), zolasartan, FI-6828K,RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, and TA-606.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more calcium channel blockers. Examples ofsuitable calcium channel blockers include nifedipine (such as ADALAT™,ADALAT CC™ and PROCARDIA™), verapamil (such as CALAN™, COVERA-HS™,ISOPTIN SR™ and VERELAN™), diltiazem (such as CARDIZEM™ CARDIZEM CD™CARDIZEM LA™, CARDIZEM SR™, DILACOR™, TIAMATE™ and TIAZAC™), isradipine(such as DYNACIRC™ and DYNACIRC CR™), amlodipine (such as NORVASC™),felodipine (such as PLENDIL™), nisoldipine (such as SULAR™), bepridil(such as VASCOR™), nicardipine, vatanidipine, clevidipine,lercanidipine, and NNC-55-0396.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more beta blockers. Examples of suitablebeta blockers include timolol (such as BLOCARDEN™) carteolol (such asCARTROL™), carvedilol (such as COREG™), nadolol (such as CORGARD™),propranolol (such as INNOPRAN XL™), betaxolol (such as KERLONE™),penbutolol (such as LEVATOL™), metoprolol (such as LOPRESSOR™ andTOPROL-XL™), atenolol (such as TENORMIN™), pindolol (such as VISKEN™),acebutolol, and bisoprolol.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more alpha blockers. Examples of suitablealpha blockers include prazosin, doxazosin (such as CARDURA™),phenoxybenzamine (such as DIBENZYLINE™), terazosin (such as HYTRIN™),CDRI-93/478 and CR-2991.

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more alpha-beta blockers. An example of asuitable alpha-beta blocker is labetalol (such as NORMODYNE™ orTRANDATE™).

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more aldosterone receptor antagonists.Examples of suitable aldosterone receptor antagonists include eplerenone(such as INSPRA™) or spironolactone (such as ALDACTONE™).

In another embodiment, one or more compounds of Formulae I or II may beco-administered with one or more renin inhibitors. Examples of suitablerenin inhibitors include aliskiren (SPP 100), SPP-500/600 and YS-004-39.

K. KITS

The present invention further comprises kits that are suitable for usein performing the methods of treatment or prevention described above. Inone embodiment, the kit contains a first dosage form comprising one ormore of the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of Formulae I or II and a diuretic.

In another embodiment, the kit of the present invention comprises one ormore compounds of Formulae I or II and an angiotensin converting enzymeinhibitor.

In another embodiment, the kit of the present invention comprises one ormore compounds of Formulae I or II and an angiotensin II receptorantagonist.

In another embodiment, the kit of the present invention comprises one ormore compounds of Formulae I or II and an aldosterone receptorantagonist.

L. INTERMEDIATES

In another embodiment, the invention relates to the novel intermediatesuseful for preparing the compounds of Formulae I or

M. GENERAL SYNTHETIC SCHEMES

The compounds of the present invention can be prepared using the methodsillustrated in the general synthetic schemes and experimental proceduresdetailed below. These general synthetic schemes and experimentalprocedures are presented for purposes of illustration and are notintended to be limiting. The starting materials used to prepare thecompounds of the present invention are commercially available or can beprepared using routine methods known in the art (such as those methodsdisclosed in COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI(published by Wiley-Interscience) or other standard reference books).

Scheme 1 below illustrates the general preparation of the pyrazolinecompounds of the present invention. Unless otherwise stated, the R¹, R⁵,R⁶, R⁸, and X substituents shown in Scheme 1 are defined as in thevarious embodiments of the invention previously disclosed above.

Method A: Preparation of α,β-unsaturated ketone 2

Method A1

Pyrrolidine (1.2 equivalents), or another cyclic secondary amine basesuch as piperidine, is added to a mixture of ketone 1 (1 equivalent) andaldehyde R¹CHO (2 equivalents) in an alcohol such as methanol (2 mL/mmolketone 1) at room temperature. About one to six hours later the mixtureis cooled to about 0° C. The resulting precipitate is filtered andwashed, for example with a cold alcohol such as methanol, to giveα,β-unsaturated ketone 2.

Method A2

A mixture of ketone 1 (1.0 equivalent) and aldehyde R¹CHO (1.2equivalents) in concentrated hydrochloric acid and ethanol is refluxedovernight. Alternatively, 4 N hydrogen chloride in dioxane can be usedinstead of concentrated hydrochloric acid. The refluxed mixture is thendiluted with water, filtered, and dried to give α,β-unsaturated ketone2.

Method A3

A solution of ketone 1 (1 equivalent) in tetrahydrofuran (approximately2.5 mL/mmol ketone 1) is added dropwise under nitrogen to a 1 M solutionof lithium hexamethyldisilazide in tetrahydrofuran (1.05 equivalents)cooled with an ice bath. Once the addition is complete, the resultingmixture is stirred for about 30 minutes. A solution of aldehyde R¹CHO(1.05 equivalents) in tetrahydrofuran (approximately 2.5 mL/mmolketone 1) is added to the mixture which is then allowed to warm to roomtemperature under stirring. After about two hours, the mixture isquenched with saturated ammonium chloride and extracted with ethylacetate. The organic layers are dried over sodium sulfate andconcentrated. The crude product is purified by silica gel flashchromatrography (ethyl acetate/heptanes) or reverse-phase HPLC(acetonitrile/water/0.1% trifluoroacetic acid) to give α,β-unsaturatedketone 2.

Method B: Pyrazoline Condensation

A mixture of α,β-unsaturated ketone 2 (1 mmol), hydrazine (R⁸NHNH₂)hydrochloride (1.2-1.5 mmol), and absolute ethanol (approximately 8mL/mmol α,β-unsaturated ketone 2) is sparged with argon and stirred atabout 80° C. for about 4 to 24 hours. The mixture is cooled to roomtemperature and filtered. The resulting solids are washed with ethanolto give pyrazoline 3.

Scheme 2 below illustrates the further derivatization of the pyrazolinecompounds prepared in accordance with Scheme 1. Unless otherwise stated,the R¹, R², R⁸, R⁵⁰, R⁵¹, R⁵² and X substituents shown in Scheme 2 aredefined as in the various embodiments of the invention previouslydisclosed above. Alternatively, pyrazolines 5, 6, 7, and 8 can beobtained using a ketone 1 starting material having the desired R⁵ and R⁶substituents (and protecting and then deprotecting those substituents asneeded using conventional protecting chemistry).

Method C: Pyrazoline Acid Derivatives

2.5 N sodium hydroxide (2 mL/mmol pyrazoline ester 4) is added to asolution of pyrazoline ester 4 (1 equivalent) in tetrahydrofuran (6mL/mmol pyrazoline ester 4) and methanol (2 mL/mmol pyrazoline ester 4).The resulting mixture is stirred at room temperature until the reactionis complete as determined by HPLC (1 to 24 hours). The mixture isconcentrated under a stream of nitrogen to approximately half of itsoriginal volume and acidified with aqueous hydrochloric acid to reducethe pH to less than about 4. The mixture is diluted with water andfiltered to give the pyrazoline acid 5.

Method D: R²-Substituted Pyrazolines

An R² substituent can be introduced by treatment of pyrazoline ester 4with a strong base, such as lithium diisopropylamide (LDA) or lithiumhexamethyldisilazide (LHMDS), and an alkylating agent, such as alkylhalide R²X. The alkylated pyrazoline ester can then be hydrolyzed asdescribed in Method C to furnish the alkylated pyrazoline acid 6.

Method E: Pyrazoline Ester Derivatives

N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2equivalents) is added under nitrogen to a mixture of pyrazoline acid 5(1 equivalent), alcohol R⁵⁰OH (1.2 equiv), and4-(dimethylamino)-pyridine (1.2 equivalents) in anhydroustetrahydrofuran (5 mL/200 mg pyrazoline acid 5). The mixture is stirredovernight, treated with excess 1N hydrochloric acid and extracted withethyl acetate. The organic layer is evaporated. The residue is dissolvedin dichloromethane and purified by silica gel chromatography with ethylacetate/heptanes. The desired fractions are combined and evaporated togive pyrazoline ester 7. If substitution at the R² position is desired,pyrazoline acid 6 can be used in place of pyrazoline acid 5.

Method F: Pyrazoline Amide Derivatives

2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(1.1 mmol), followed by N,N-diisopropylethylamine (1.5 mmol), are addedunder nitrogen at room temperature to a solution of pyrazoline acid 5 (1mmol) in 5 mL of anhydrous dimethylformamide. The mixture is stirred forabout five minutes and amine NHR⁵¹R⁵² (1.5 mmol) is added. The mixtureis stirred for another hour. The mixture is then filtered and purifiedby reverse-phase HPLC (acetonitrile/water/0.1% trifluoroacetic acid).The fractions containing pure product are combined and lyophilized togive pyrazoline amide 8. If substitution at the R² position is desired,pyrazoline acid 6 can be used in place of pyrazoline acid 5.

Method G: Chiral Resolution

The pyrazoline compounds of the present invention (including theprecursor intermediates) can have two or more chiral centers. Where thesynthesis yields a compound as a mixture of enantiomers ordiastereomers, the desired enantiomer or diastereomer (or the desiredenantiomerically-enriched mixture or diastereomerically-enrichedmixture) can be obtained using conventional chiral resolution methods.Conventional methods that can be employed include chromatography (suchas HPLC) or supercritical fluid chromatography on an asymmetric resin.Concentration of the luate affords the enriched mixture. Thestereoismomerically-enriched pyrazoline can be further derivatized asdepicted in Scheme 2 in a manner analogous to that for pyrazolines 5 and6.

Schemes 3a, 3b, and 3c below illustrate several alternative syntheticschemes that can be used to prepare the R⁸NHNH₂ hydrazine reagentemployed in Scheme 1. Unless otherwise stated, the R⁸¹, R⁸², R⁸⁴, andR⁸⁵ substituents shown in Scheme 1 are defined as in the variousembodiments of the invention previously disclosed above, and Arrepresents aryl or heteroaryl.

Method H: Preparation from a Halogenated Aryl Nitrile

A solution of a para-halogen, substituted aryl/heteroaryl nitrile isrefluxed with an excess of hydrazine monohydrate in an alcohol, such asethanol. Upon completion of the reaction, the mixture is diluted withwater and filtered. The aryl/heteroaryl hydrazine can then be convertedto the hydrochloride salt by treatment with an equivalent anhydroushydrogen chloride in diethyl ether. The resultant hydrazinehydrochloride salt is isolated by filtration.

Method I: Preparation from an Aniline

Aryl or heteroaryl anilines can be converted to the corresponding arylor heteroaryl hydrazine by diazotization and subsequent reduction.Accordingly, an ice-cold mixture of the aniline in a strong aqueousacid, such as concentrated hydrochloric acid or aqueous sulfuric acid,is treated with sodium nitrite (usually 1 to 1.1 equivalents). After ashort period of time, usually 15 to 60 minutes, the resultant mixture isadded to an ice-cold suspension of excess stannous chloride in a strongaqueous acid, such as concentrated hydrochloric acid or aqueous sulfuricacid. The mixture is then allowed to warm to room temperature for a fewhours. The mixture is then neutralized with aqueous base and extractedwith a suitable organic solvent such as ethyl acetate to isolate thearyl/heteroaryl hydrazine. The aryl/heteroaryl hydrazine can then beconverted to the hydrochloride salt by treatment with an equivalentanhydrous hydrogen chloride in diethyl ether. The resultant hydrazinehydrochloride salt is isolated by filtration.

Methods J and K: Preparation from Arylhalides

Aryl or heteroaryl hydrazines can be obtained by coupling anaryl/heteroaryl halide with benzophenone hydrazone in the presence of apalladium catalyst, a phosphine ligand, and a base (Mauger and Mignani(2005) Advanced Synthesis and Catalysis 347 (6), 773-782; Haddad, et al.(2004) Tetrahedron Lett. 45, 5935-7; Haddad and Baron (2002) 43(12),2171-2173; Wagaw et al. (1999) 121(44) 10251-10263 (Method J). Thecoupled product is subsequently hydrolyzed by refluxing in aqueous acidand an organic co-solvent, such as tetrahydrofuran, to yield thearyl/heteroaryl hydrazine (Method K).

Scheme 4 below illustrates a synthetic scheme that can be used toprepare ketone 11 (i.e., ketone 1 wherein R⁵ is methoxycarbonyl and R⁶is hydrogen) for use as a reagent in Scheme 1.

Methods L and M: Preparation of Tetralone 11

In a manner similar to that described by Gerlach and Wollmann inTetrahedron Letters (1992), 33(38), 5499-5502, ketone 11 can be preparedfrom phenolic ketone 9 by triflation with triflic anhydride and pyridinein a suitable organic solvent, such as methylene chloride and heptane,followed by subsequent palladium-catalyzed carbonylation with carbonmonoxide in dimethylformamide and methanol.

The synthesis of other ketones useful in the preparation of pyrazolinesdescribed in Scheme 1 are described in the literature (for example, seeReiter et al., Bioorganic and Medicinal Chemistry Letters, 7, 2307-2312;Koch et al., U.S. Pat. No. 5,550,152 (1996); Ferraz et al. Tetrahedron(2003) 59(31) 5817-5821); Cannon et al., Journal of Medicinal Chemistry(1989) 32(9), 2210-2214; and Beugelmans, et al. Journal of OrganicChemistry (1985), 50(24), 4933-4938). Such ketones may be furtherderivatized by using routine methods known in the art (such as thosemethods disclosed in COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI(published by Wiley-Interscience) or other standard reference books).

Scheme 5 below illustrates a synthetic scheme that can be used toprepare pyrazoline acid 14 (i.e., pyrazoline acid 5a wherein X is carbonand the position of the R⁵ carboxy substituent is as shown) which can befurther derivatized as shown in Scheme 2.

Method N: Pyrazoline Condensation

Pyrazoline 13a can be obtained by condensation of R⁸NHNH₂ withα,β-unsaturated ketone 12 (prepared as described in Scheme 1, Method A1)in a refluxing alcohol, such as methanol or ethanol, and one to twoequivalents of 4 N hydrogen chloride in dioxane or other suitable sourcehydrogen chloride. After 4 to 24 hours, the reaction mixture is cooled,and pyrazoline ester 13a is isolated by filtration.

Method O: Chiral Resolution

Stereoisomerically-enriched pyrazoline esters 13b generally can beobtained using chromatography such as HPLC on an asymmetric resin with amobile phase comprising a hydrocarbon or halogenated hydrocarbon, suchas heptane, hexane, or dichloromethane, and further containingisopropanol (from about 0% to about 50% by volume, typically from about2% to about 20% by volume) and alkylamine (e.g., from 0 to 5% by volume,typically about 0.1% diethylamine by volume).Stereoisomerically-enriched compounds generally can also be obtainedusing supercritical fluid chromatography (SFC) on an asymmetric resinwith a mobile phase comprising an alcohol (about 30% to about 60% byvolume, typically about 50% by volume) and carbon dioxide. Concentrationof the eluate affords the enriched mixture 13b.

Method P: Hydrolysis

A mixture of pyrazoline ester 13b in a suitable organic solvent such astetrahydrofuran is treated with sodium trimethylsilanoate, usually oneto three equivalents, under an inert atmosphere. The reaction isconducted between room temperature and 50° C.

N. COMPOUND EXAMPLES Preparation 1

2-chloro-4-hydrazinylbenzonitrile hydrochloride

A mixture of 2-chloro-4-fluorobenzonitrile (20.0 g, 129 mmol), hydrazinemonohydrate (9.4 mL, 193 mmol), and ethanol (80 mL) was refluxed for 4hours. The mixture was diluted with water (200 mL). The precipitate wasfiltered, washed with water, and dried to give an off-white solid (16.8g). The solid was suspended in diethyl ether (400 mL) and treated with2N Hydrogen chloride/ether (50 mL, 100 mmol). The precipitate wasfiltered, washed with diethyl ether, and dried to give2-chloro-4-hydrazinylbenzonitrile hydrochloride as a white solid (16.3g, 79.9 mmol, 62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.63 (br. s.,3H), 9.17 (br. s., 1H), 7.74 (d, J=8.9 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H),6.92 (dd, J=8.6, 2.1 Hz, 1H). ES-MS m/z 168 (M+H).

Preparation 2

4-hydrazinyl-2-methylbenzonitrile hydrochloride

A mixture of 4-fluoro-2-methylbenzonitrile (20.4 g, 151 mmol), hydrazinemonohydrate (14.6 mL, 302 mmol), and ethanol (80 mL) was refluxed for 48hours. The mixture was diluted with water (200 mL). The precipitate wasfiltered, washed with water, and dried to give an off-white solid (16.1g). The solid was suspended in diethyl ether (400 mL) and treated with2N Hydrogen chloride/ether (55 mL, 110 mmol). The precipitate wasfiltered, washed with diethyl ether, and dried to give4-hydrazinyl-2-methylbenzonitrile hydrochloride as a white solid (15.6g, 85.0 mmol, 56% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.42 (br. s.,1H), 8.33 (br. s., 3H), 7.51 (d, J=8.6 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H),6.74 (dd, J=8.6, 2.4 Hz, 1H), 2.35 (s, 3H). ES-MS m/z 148 (M+H).

Preparation 3

4-hydrazinyl-2-(trifluoromethyl)benzonitrile hydrochloride

The title compound was prepared according to the procedure inPreparation 1 from 4-fluoro-2-(trifluoromethyl)benzonitrile (1.89 g, 10mmol), instead of 2-chloro-4-fluorobenzonitrile, at 80° C. to give anoff-white solid (1.89 g, 8.0 mmol, 80% yield). ES-MS m/z 202 (M+H).

Preparation 4

4-hydrazinyl-2-methoxybenzonitrile hydrochloride

The title compound was prepared according to the procedure inPreparation 1 from 4-fluoro-2-methoxybenzonitrile (4.97 g, 32.9 mmol),instead of 2-chloro-4-fluorobenzonitrile, refluxing overnight to give4-hydrazinyl-2-methoxybenzonitrile hydrochloride (3.54 g, 17.8 mmol. 54%yield) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.82 (s, 3H) 6.44 (dd, J=8.46,2.01 Hz, 1H) 6.64 (d, J=2.15 Hz, 1H) 7.41 (d, J=8.32 Hz, 1H) 7.99 (s,2H) 8.40 (s, 1H). ES-MS m/z 164 (M+H).

Preparation 5

5-hydrazinylpicolinonitrile dihydrochloride

To a solution of 5-aminopicolinonitrile (1.0 g, 8.4 mmol) in 20%sulfuric acid aq. (20 mL) at 0° C., sodium nitrite (590 mg, 9.2 mmol) inwater (3 mL) was slowly added, keeping the temperature below 10° C. Thissolution was stirred on an ice bath for 30 minutes and then treatedslowly with an ice cold solution of tin(II) chloride dihydrate (5.7 g,25.2 mmol) in 20% sulfuric acid (20 mL) keeping the temperature below10° C. The solution was stirred at 0° C. for 15 minutes and warmed toroom temperature over 30 minutes. The reaction was neutralized withammonium hydroxide, and the resulting tin salts were filtered off. Thefiltrate was extracted three times with ethyl acetate, dried overmagnesium sulfate, filtered and evaporated. The resulting solid residuewas dissolved in ethyl acetate and tetrahydrofuran and treated with 4 NHydrogen chloride in dioxane (approximately 3 mL). The mixture wasevaporated and the resulting solid was triturated with diethyl ether anddried on the high vacuum overnight to give a 2:1 mixture of5-hydrazinylpicolinonitrile dihydrochloride to starting material (875mg). ES-MS m/z 135 (M+H).

Preparation 6

6-hydrazinyl-2-methylnicotinonitrile

To a suspension of 6-chloro-2-methylnicotinonitrile (6.2 mmol) in 6.2 mLof ethanol, hydrazine monohydrate (9.3 mmol) was added. The resultingmixture was then heated to 80° C. overnight. The mixture was cooled toroom temperature and 2 mL of water was added. It was heated to 80° C.again to a clear solution and then allowed to cool down to roomtemperature and finally in an ice-bath. The solid was collected byfiltration, washed with cold 50% ethanol, and dried under vacuum to give550 mg of the desired solid product. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.41 (s, 3H), 4.41 (s, 2H), 6.60 (br. s., 1H), 7.66 (d, J=8.59 Hz, 1H),8.47 (s, 1H); ES-MS m/z 149 (M+H).

Preparation 7

2-(bromomethyl)-4-fluorobenzonitrile

A solution of 2-methyl-4-fluoro-benzonitrile (3.5 g, 25.9 mmol) in 40 mLof carbon tetrachloride was treated with N-Bromosuccinimide (4.6 g, 25.9mmol) and benzoylperoxide (157 mg, 0.65 mmol). The mixture was heated toreflux for 3 hours, cooled to room temperature and allowed to stirovernight. The solids were filtered off and washed with carbontetrachloride. The filtrate was condensed and purified by normal phaseflash column chromatography on a 50 g silica gel column (5-50% ethylacetate/hexanes gradient). Two peaks separated. It was determined thatthe second eluting peak is the desired product. Pure fractions of thispeak were pooled and concentrated in vacuo to yield2-(bromomethyl)-4-fluorobenzonitrile (1.35 g, 0.63 mmol, 25% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.79 (s, 2H), 7.44 (dt,J=8.59, 2.69 Hz, 1H), 7.68 (dd, J=9.53, 2.55 Hz, 1H), 8.01 (dd, J=8.59,5.64 Hz, 1H).

Preparation 8

4-fluoro-2-(methoxymethyl)benzonitrile

A solution of 2-(bromomethyl)-4-fluorobenzonitrile (501 mg, 2.3 mmol) inmethanol (5 mL) was treated with sodium methoxide (5.6 mL of 0.5 Msolution in methanol, 2.81 mmol) and stirred for 1 hour at roomtemperature then heated to 55° C. for 2 hours. The mixture was cooled toroom temperature, condensed to dryness and directly purified by normalphase flash column chromatography on a 20 g silica gel column (5-60%ethyl acetate/hexanes gradient). Pure fractions were pooled andconcentrated in vacuo to yield 4-fluoro-2-(methoxymethyl)benzonitrile(110 mg, 0.66 mmol, 28% yield) as an oil. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.97 (dd, J=8.46, 5.50 Hz, 1H), 7.46 (dd, J=9.53, 2.55 Hz, 1H), 7.39(td, J=8.59, 2.69 Hz, 1H), 4.58 (s, 2H), 3.37 (s, 3H).

Preparation 9

4-hydrazinyl-2-(methoxymethyl)benzonitrile hydrochloride

A mixture of 4-fluoro-2-(methoxymethyl)benzonitrile (110 mg, 0.67 mmol),hydrazine monohydrate (133 mg, 0.13 mL, 2.6 mmol) and ethanol (5 mL) washeated to reflux overnight. The mixture was cooled to room temp andcondensed. The residue was dissolved in methanol and treated with 2.0 NHydrogen chloride in diethyl ether. The solvent was removed and thesolid was dried to give 4-hydrazinyl-2-(methoxymethyl)benzonitrilehydrochloride as an off-white solid.

Preparation 10

2-((dimethylamino)methyl)-4-fluorobenzonitrile

A mixture of 2-(bromomethyl)-4-fluorobenzonitrile (423 mg, 1.9 mmol) and2.0 M dimethylamine (4 mL) was stirred at room temperature for thirtyminutes. The mixture was then concentrated, purified by normal phaseflash column chromatography, on a 20 g silica gel column (5-45% ethylacetate/hexanes gradient), and concentrated in vacuo to yield2-((dimethylamino)methyl)-4-fluorobenzonitrile (241 mg, 1.35 mmol, 68%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.92 (dd, J=8.59, 5.37 Hz, 1H), 7.42(dd, J=9.94, 2.69 Hz, 1H),7.35 (td, J=8.46, 2.69 Hz, 1H), 3.56 (s, 2H),2.19 (s, 6H).

Preparation 11

2-((dimethylamino)methyl)-4-hydrazinylbenzonitrile dihydrochloride

A mixture of 2-((dimethylamino)methyl)-4-fluorobenzonitrile (241 mg,1.35 mmol), hydrazine monohydrate (101 mg, 0.10 mL, 2.0 mmol) andethanol (5 mL) was heated overnight at 90° C. The mixture was cooled toroom temperature and concentrated to dryness. The residue was dissolvedin diethyl ether and treated with 2.0 M Hydrogen chloride in diethylether. The resulting solid was filtered and dried to give2-((dimethylamino)methyl)-4-hydrazinylbenzonitrile dihydrochloride (430mg, 1.63 mmol, >100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.26 (s,1H), 7.80 (d, J=8.59 Hz, 1H), 7.36 (d, J=2.15 Hz, 1H), 7.08 (dd, J=8.59,2.15 Hz, 1H), 4.35 (s, 2H), 2.78 (s, 6H). ES-MS m/z 191 (M+H).

Preparation 12

2-(benzyloxy)-4-fluorobenzonitrile

Benzyl alcohol (3.25 g, 30 mmol) was slowly added to a stirredsuspension of sodium hydride (1.15 g, 28.7 mmol) in toluene (50 mL) atroom temperature. The mixture was stirred for 30 minutes and then2,4-difluorobenzonitrile was added all at once and stirring continuedovernight. The mixture was quenched with water, extracted three timeswith ethyl acetate, washed with brine, dried over magnesium sulfate,filtered and condensed. The crude product was dissolved in hot ethylacetate and triturated with hexanes to give2-(benzyloxy)-4-fluorobenzonitrile (5.4 g, 23.8 mmol, 88% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.30 (s, 2H), 6.99 (td,J=8.46, 2.42 Hz, 1H), 7.29-7.51 (m, 6H), 7.86 (dd, J=8.59, 6.44 Hz, 1H).

Preparation 13

2-(benzyloxy)-4-hydrazinylbenzonitrile

A solution of 2-(benzyloxy)-4-fluorobenzonitrile (4.8 g, 21 mmol), inethanol (80 mL) was treated with hydrazine monohydrate (2.6 g, 2.5 mL,53 mmol) and heated to reflux for 3 days. The mixture was cooled to roomtemperature and concentrated. Water was added and the residue wasextracted three times with ethyl acetate, dried over magnesium sulfate,filtered and condensed to give 2-(benzyloxy)-4-hydrazinylbenzonitrile(3.8 g, 15.8 mmol, 75% yield) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) ppm 4.27 (s, 2H), 5.16 (s, 2H), 6.36 (dd, J=8.73, 1.75 Hz, 1H),6.61 (d, J=1.61 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 7.32-7.51 (m, 5H),7.78 (s, 1H). ES-MS m/z 240 (M+H)

Preparation 14

cyclopent-1-enecarbaldehyde

To a solution of sodium periodate (28.3 g, 0.13 mol) in water (250 mL)was added an ethyl ether solution (150 mL) of 1,2-cyclohexanediol (12.0g, 0.10 mol). The solution was stirred for thirty minutes at ambienttemperature. To this solution was added 20% aqueous potassium hydroxide(40 mL) and the solution stirred for one hour. The layers were separatedand the organic layer was washed with water and brine and dried overmagnesium sulfate. Concentration in vacuo providedcyclopent-1-enecarbaldehyde as a yellow oil (6.0 g, 62% yield).Reversed-phase HPLC on 4.6×50 mm C-18 column, t_(R)=0.825 minutes (10 to90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254nm, at 20° C.); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83-1.93 (m, 2H), 2.36(td, J=7.65, 2.15 Hz, 2H), 2.50-2.59 (m, 2H), 7.01-7.08 (m, 1H), 9.73(s, 1H).

Preparation 15

methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

A solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid(5.14 g, 27.0 mmol) (Peakdale Molecular) in 4N hydrochloric acid inmethanol was heated to reflux for eighteen hours. The solution wasreturned to ambient temperature and concentrated in vacuo. The residuewas diluted with ethyl acetate and washed with saturated sodiumbicarbonate solution and saturated sodium chloride and dried overmagnesium sulfate. Filtration followed by concentration in vacuoprovided methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as abrown solid (4.76 g, 86% yield). Reversed-phase HPLC on 4.6×50 mm C-18column, t_(R)=1.90 minutes (10 to 90% acetonitrile/water over 4 minutesat 4 mL/minute with detection 254 nm, at 20° C.); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.99-2.08 (m, 2H), 2.58-2.66 (m, 2H), 2.99 (t, J=6.04 Hz,2H), 3.85 (s, 3H), 7.83-7.87 (m, 1H), 7.91 (d, J=0.81 Hz, 1H), 7.92-7.97(m, 1H).

Preparation 16

ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared according to Method A2. The crudeprecipitate was a mixture of ethyl5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate, ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylateand6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid. The mixture was combined with 4-fluorobenzaldehyde (0.5 mL),ethanol (40 mL) and 4N Hydrogen chloride/dioxane (10 mL) and wasrefluxed for 20 hours. The solution was poured into 200 mL water,filtered, and dried to give ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylateas an off-white solid (826 mg, 2.55 mmol, 49% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33 (t, J=7.12 Hz, 3H), 3.06 (m, 4H), 4.34 (q, J=6.98Hz, 2H), 7.31 (t, J=8.86 Hz, 2H), 7.62 (dd, J=8.59, 5.64 Hz, 2H), 7.74(s, 1H), 7.94 (m, 2H), 8.06 (d, J=8.59 Hz, 1H). ES-MS m/z 325 (M+H).

Preparation 17

ethyl7-(4-fluorobenzylidene)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared according to Method A2 from8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid and4-fluorobenzaldehyde as an off-white solid (64% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.34 (t, J=7.12 Hz, 3H), 3.05 (m, 4H), 4.34 (q, J=7.25Hz, 2H), 7.30 (m, 2H), 7.54 (d, J=7.79 Hz, 1H), 7.61 (m, 2H), 7.74 (s,1H), 8.10 (dd, J=7.92, 2.01 Hz, 1H), 8.49 (d, J=1.88 Hz, 1H). ES-MS m/z325 (M+H).

Preparation 18

methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

To a solution of methyl5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.4 g, 16.7 mmol) inmethanol (30 mL) was added cyclopentanecarboxaldehyde (3.3 g, 33.3 mmol)and pyrrolidine (2.78 mL, 33.3 mmol). The solution was stirred fortwenty hours at ambient temperature. The reaction was recharged with 0.5mL of cyclopentanecarboxaldehyde. The resulting precipitate wascollected by vacuum filtration to provide methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylateas a solid (2.8 g, 60% yield). LC/MS on 4.6×50 mm C-18 column,t_(R)=6.71 minutes (10 to 90% acetonitrile/water over 8 minutes at 2mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.24-1.39 (m, 2H), 1.52-1.74 (m, 4H), 1.76-1.89(m, 2 H), 2.77 (t, J=5.77 Hz, 2H), 2.79-2.90 (m, 1H), 2.97 (t, J=6.44Hz, 2H), 3.85 (s, 3H), 6.71 (d, J=9.94 Hz, 1H), 7.88 (d, J=6.44 Hz, 1H),7.91 (s, 1H), 7.98 (d, J=8.06 Hz, 1H).

Preparation 19

methyl6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(600 mg, 2.9 mmol) in tetrahydrofuran (10 mL) was cooled to ice bathtemperature and treated with 1.0 M lithium hexamethyldisilazide intetrahydrofuran (5 mL). After stirring for twenty minutes,cyclobutanecarboxaldehyde (J. Med. Chem. 1989, 32, 1001-6) (24 mL of 0.5M solution in tetrahydrofuran) was slowly added and the mixture allowedto warm to room temperature and stir for 3 days. The mixture was pouredinto water, extracted three times with ethyl acetate, washed with brine,dried over magnesium sulfate, filtered and concentrated. The crudeproduct was purified by normal phase flash column chromatography on a 50g silica gel column (5-50% ethyl acetate/hexanes gradient). Purefractions were pooled and concentrated in vacuo to yield methyl6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(300 mg, 1.1 mmol, 38% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81-2.03(m, 4H), 2.14-2.27 (m, 2H), 2.71 (t, J=6.58 Hz, 2H), 2.93-3.00 (m, 2H),3.34-3.44 (m, 1H), 3.88 (s, 3H), 6.91 (d, J=9.13 Hz, 1H), 7.84-7.95 (m,2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 271 (M+H).

Preparation 20

(±)-methyl5-oxo-6-((tetrahydrofuran-3-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

To a solution of methyl5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (240 mg, 1.2 mmol) inmethanol (3 mL) was added (±)-tetrahydrofuran-3-carboxaldehyde (240 mg,2.4 mmol) and pyrrolidine (0.20 mL, 2.4 mmol). The solution was stirredfor twenty hours at ambient temperature and for four hours at 45° C. Thereaction was concentrated in vacuo. Chromatography (on silica, ethylacetate/hexane) provided (±)-methyl5-oxo-6-((tetrahydrofuran-3-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylateas an orange oil (200 mg, 58% yield). LC/MS on 4.6×50 mm C-18 column,t_(R)=2.52 minutes (10 to 90% acetonitrile/water over 4 minutes at 4mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 287 (M+H).

Preparation 21

methyl5-oxo-6-((tetrahydro-2H-pyran-4-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(2.9 mmol), tetrahydro-pyran-4-carbaldehyde (3.2 mmol), and piperidine(3.2 mmol) in 6 mL of methanol was heated to 65° C. overnight. Thecooled mixture was diluted with ethyl acetate, washed with water andbrine, dried over sodium sulfate, and concentrated. The residue waspurified by silica gel, eluting with ethyl acetate in hexane from 10% to40%, to give 430 mg of the desired product. ES-MS m/z 301 (M+H).

Preparation 22

tert-butyl4-((6-(methoxycarbonyl)-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)piperidine-1-carboxylate

Prepared according to the procedure of Preparation 21 except usingtert-butyl 4-formylpiperidine-1-carboxylate, instead of methyl5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate, to give the titlecompound in 71% yield. ES-MS m/z 422 (M+Na).

Preparation 23

methyl6-(5-methyl-2-furylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared according to Method A3 from5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396mg, 1.9 mmol) and 5-methyl-2-furaldehyde (192 mg, 2.0 mmol). ES-MS m/z297 (M+H).

Preparation 24

methyl6-(cyclopent-1-en-1-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared from5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396mg, 1.9 mmol) and 1-cyclopentene carbaldehyde (220 mg, 2.0 mmol)according to Method A3 in 70% yield. ES-MS m/z 283 (M+H)

Preparation 25

methyl6-(2-furylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared from5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396mg, 1.9 mmol) and 2-furaldehyde (192 mg, 2.0 mmol) according to MethodA3 in 80% yield. ES-MS m/z 283 (M+H).

Preparation 26

methyl6-(3-furylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared from5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396mg, 1.9 mmol) and 3-furaldehyde (192 mg, 2.0 mmol) according to MethodA3 in 80% yield. ES-MS m/z 283 (M+H)

Preparation 27

methyl6-[(2-methyl-1,3-thiazol-5-yl)methylene]-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared from5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396mg, 1.9 mmol) and 2-methyl-1,3-thiazole-5-carbaldehyde (220 mg, 2.0mmol) according to Method A3 in 60% yield. ES-MS m/z 314 (M+H)

Preparation 28

methyl6-(isoxazol-5-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

The title compound was prepared from5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396mg, 1.9 mmol) and isoxazole-5-carbaldehyde (200 mg, 2.0 mmol) accordingto Method A3 in 55% yield. ES-MS m/z 284 (M+H)

Preparation 29

ethyl[3-(4-fluorobenzylidene)-4-oxo-3,4-dihydro-2H-chromen-7-yl]acetate

The title compound was prepared frommethyl[4-oxo-3,4-dihydro-2H-chromen-7-yl]acetate (L. A. Reiter et al.Biorganic and Medicianal Chemistry Letters, 1997, 7 2307-2312) and4-fluorobenzaldehyde according to Method A2 in 45% yield. ES-MS m/z 341(M+H).

Preparation 30

methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate

The title compound was prepared from methyl 4-oxochroman-7-carboxylate(Koch, K., and Biggers, M. S. J. Org. Chem. 1994, 59, 1216-1218) and4-fluorobenzaldehyde according to Method A2 using methanol and 4 NHydrogen chloride/dioxane. Off-white solid (78c/0 yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.88 (s, 3H), 5.48 (s, 1H), 7.35 (t, J=8.59 Hz, 2H),7.50-7.61 (m, 3H), 7.66 (d, J=7.25 Hz, 1H), 7.80 (s, 1H), 8.01 (d,J=8.06 Hz, 1H).

Preparation 31

methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate

The title compound was prepared according to General Method A1 frommethyl 4-oxochroman-7-carboxylate (Koch, K., and Biggers, M. S. J. Org.Chem. 1994, 59, 1216-1218) and cyclopentanecarboxaldehyde as anoff-white solid (2.12 g, 7.42 mmol, 76% yield). ES-MS m/z 287 (M+H).

Preparation 32

methyl 3-(2-methylpropylidene)-4-oxochroman-7-carboxylate

The title compound was prepared according to General Method A1 frommethyl 4-oxochroman-7-carboxylate (Koch, K., and Biggers, M. S. J. Org.Chem. 1994, 59, 1216-1218) and isobutyraldehyde. After stirringovernight, the solution was partitioned between 1 N Hydrogen chlorideand ethyl acetate. The organic layers were washed with 1 N Hydrogenchloride and brine, dried (sodium sulfate), and concentrated. The crudeproduct was purified by flash chromatography (0 to 20% ethylacetate/hexanes) to give methyl3-(2-methylpropylidene)-4-oxochroman-7-carboxylate as an oily solid (730mg, 2.8 mmol, 58% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.95 (d, J=8.2Hz, 1H), 7.62 (dd, J=8.2, 1.6 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 6.65 (dt,J=10.3, 1.7 Hz, 1H), 5.22 (d, J=1.6 Hz, 2H), 3.88 (s, 3H), 2.73-2.86 (m,1H), 1.04 (d, J=6.6 Hz, 6H). ES-MS m/z 261 (M+H).

Preparation 33

methyl 3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate

The title compound was prepared according to Method A1 from methyl4-oxochroman-7-carboxylate (Koch, K., and Biggers, M. S. J. Org. Chem.1994, 59, 1216-1218) and cyclopropanecarboxaldehyde as an off-whitesolid (1.14 g, 91% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.86 (m,2H), 1.00-1.11 (m, 2H), 1.80-1.95 (m, 1H), 3.87 (s, 3H), 5.31 (d, J=1.56Hz, 2H), 6.27 (d, J=11.33 Hz, 1H), 7.52 (d, J=1.56 Hz, 1H), 7.60 (dd,J=8.20, 1.56 Hz, 1H), 7.94 (d, J=8.20 Hz, 1 H). ES-MS m/z 259 (M+H).

Preparation 34

methyl 3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate

To a solution of methyl 4-oxochroman-7-carboxylate (500 mg, 2.4 mmol) inmethanol (5 mL) was added cyclopent-1-enecarbaldehyde (465 mg, 4.8 mmol)and pyrrolidine (0.40 mL, 4.8 mmol). The solution was stirred for onehour at ambient temperature. The resulting brown precipitate wascollected by vacuum filtration and dried to give methyl3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate (444 mg, 64%yield). LC/MS on 4.6×50 mm C-18 column, t_(R)=6.49 minutes (10 to 90%acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm,at 50° C.); ES-MS m/z 285 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.88-1.99 (m, 2H), 2.43 (d, J=13.16 Hz, 2H), 2.63 (t, J=6.98 Hz, 2H),3.85 (s, 3 H), 5.36 (s, 2H), 6.45 (br. s., 1H), 7.37 (s, 1H), 7.49 (d,J=1.34 Hz, 1H), 7.60 (dd, J=8.06, 1.61 Hz, 1H), 7.93 (d, J=8.32 Hz, 1H).

Preparation 35

3-(4-fluorobenzylidene)-4-oxochroman-7-yl trifluoromethanesulfonate

The title compound was prepared according to Method A1 from4-oxochroman-7-yl trifluoromethanesulfonate (500 mg, 1.7 mmol) (U.S.Pat. No. 5,550,152; Example 1, Step C) and 4-fluorobenzaldehyde (0.21mL, 2.0 mmol) to give 3-(4-fluorobenzylidene)-4-oxochroman-7-yltrifluoromethanesulfonate (260 mg, 0.65 mmol, 40% yield) as a solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 5.52 (d, J=1.88 Hz, 2H), 7.25 (dd, J=8.73,2.28 Hz, 1H), 7.31-7.39 (m, 3H), 7.56 (dd, J=8.73, 5.50 Hz, 2H), 7.80(s, 1H), 8.06 (d, J=8.86 Hz, 1H). ES-MS m/z 403 (M+H).

Preparation 36

N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide

A mixture of 6-acetamido-1-tetralone (200 mg, 0.98 mmol) andcyclopentanecarboxaldehyde (0.21 mL, 1.9 mmol) in methanol (2 mL) wastreated with pyrrolidine (0.25 mL, 2.9 mmol) at room temperature for 1hour then heated at 55° C. overnight. The mixture was cooled to roomtemperature, treated with 1N Hydrogen chloride (4 mL) was filtered thrua Chem Elute tube (CE101 1) eluting with 90% dichloromethane/10% ethylacetate and condensed filtrate to give(E)-N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide(200 mg, 0.71 mmol, 72% n yield) as a tan foam. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.25-1.44 (m, 2H), 1.52-1.76 (m, 4H), 1.77-1.90 (m, 2H),2.08 (s, 3 H), 2.70-2.92 (m, 5H), 6.63 (d, J=9.67 Hz, 1H), 7.49 (dd,J=8.59, 2.15 Hz, 1H), 7.59-7.66 (m, 1H), 7.86 (d, J=8.59 Hz, 1H), 10.23(s, 1H). ES-MS m/z 284 (M+H).

Example 1

ethyl2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 16; 324 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrilehydrochloride (Preparation 1; 306 mg, 1.5 mmol) according to Method B(yellow solid, 394 mg, 0.830 mmol, 83% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.80 (m, 1H), 1.31 (t, J=7.12 Hz, 3H), 1.79 (m, 1H), 2.95 (m, 2H),3.97 (ddd, J=13.49, 11.21, 4.83 Hz, 1H), 4.31 (q, J=6.98 Hz, 2H), 5.94(d, J=11.28 Hz, 1H), 7.15 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.80 (s,1H), 7.85 (dd, J=8.19, 1.75 Hz, 1H), 8.16 (d, J=8.06 Hz, 1H). ES-MS m/z474 (M+H).

Example 2

2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from ethyl2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate(Example 1; 330 mg, 0.696 mmol) according to Method C (yellow solid, 297mg, 0.666 mmol, 96% yield). The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (m, 1H), 1.79 (m, 1H), 2.93(m, 2H), 3.96 (m, 1H), 5.93 (d, J=11.01 Hz, 1H), 7.15 (m, 6H), 7.66 (d,J=8.59 Hz, 1H), 7.78 (s, 1H), 7.83 (dd, J=8.19, 1.48 Hz, 1H), 8.14 (d,J=8.06 Hz, 1H), 13.07 (s, 1H). ES-MS m/z 446 (M+H).

Example 3

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 2 using chiral resolution (e.g., Method G).

Example 4

(3S,3aS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 2 using chiral resolution (e.g., Method G).

Example 5

2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-8-carboxylicacid

The title compound was prepared from ethyl7-(4-fluorobenzylidene)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 17) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride(Preparation 1) according to Method B and Method C (off-white solid, 299mg). The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-8-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (qd, J=13.02, 5.24 Hz, 1H),1.79 (m, 1H), 2.95 (m, 2H), 3.96 (m, 1H), 5.92 (d, J=11.01 Hz, 1H), 7.15(m, 6H), 7.35 (d, J=8.06 Hz, 1H), 7.64 (d, J=8.86 Hz, 1H), 7.86 (dd,J=8.06, 1.61 Hz, 1H), 8.57 (d, J=1.61 Hz, 1H), 13.17 (s, 1 H). ES-MS m/z446 (M+H).

Example 6

2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 16; 324 mg, 1.0 mmol) and 4-hydrazinyl-2-methylbenzonitrilehydrochloride (Preparation 2; 275 mg, 1.5 mmol) according to Method Band Method C (solid, 290 mg, 0.68 mmol, 68% yield). The title compoundwas largely present as(±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71-0.87 (m, 1H), 1.76-1.84 (m,1H), 2.36 (s, 3H), 2.84-3.01 (m, 2H), 3.86-3.98 (m, 1H), 5.87 (d,J=11.28 Hz, 1H), 6.65-7.36 (m, 6H), 7.48 (d, J=8.60 Hz, 1H), 7.76 (s,1H), 7.82 (dd, J=8.19, 1.75 Hz, 1H), 8.10 (d, J=8.33 Hz, 1H). ES-MS m/z426 (M+H).

Example 7

(3R,3aR)-2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 6 using chiral resolution (e.g., Method G).

Example 8

(3S,3aS)-2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 6 using chiral resolution (e.g., Method G).

Example 9

2-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 16; 324 mg, 1.0 mmol) and4-hydrazinyl-2-(trifluoromethyl)benzonitrile hydrochloride (Preparation3; 356 mg, 1.5 mmol) according to Method B and Method C (solid, 366 mg,0.76 mmol, 76% yield). The title compound was largely present as (±)(3RS,3aRS)-2-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.91 (m, J=13.17, 5.37 Hz,1H), 1.75-1.84 (m, 1H), 2.94 (d, J=2.96 Hz, 2H), 3.94-4.05 (m, 1H), 6.00(d, J=11.02 Hz, 1H), 7.15 (s, 6H), 7.79 (s, 1H), 7.81-7.88 (m, 2H), 8.15(d, J=8.33 Hz, 1H). ES-MS m/z 480 (M+H).

Example 10

2-(4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 16; 324 mg, 1.0 mmol) and 4-hydrazinylbenzonitrilehydrochloride (Aldrich; 254 mg, 1.5 mmol) according to Method B andMethod C (solid, 294 mg, 0.72 mmol, 72% yield). The title compound waslargely present as(±)-(3RS,3aRS)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70-0.88 (m, 1H), 1.74-1.84 (m,1H), 2.82-3.01 (m, 2H), 3.86-3.99 (m, 1H) 5.87 (d, J=11.28 Hz, 1H), 7.13(s, 6H), 7.57 (d, J=9.14 Hz, 2H), 7.74 (s, 1H), 7.78-7.83 (m, 1H), 8.05(d, J=8.33 Hz, 1H). ES-MS m/z 412 (M+H).

Example 11

(3R,3aR)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 10 using chiral resolution (e.g., Method G).

Example 12

(3S,3aS)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 10 using chiral resolution (e.g., Method G).

Example 13

3-(4-fluorophenyl)-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

To ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 16; 303 mg, 1.07 mmol) and6-hydrazinyl-3,4-dihydroisoquinolin-1(2H)-one (240 mg, 1.3 mmol) (U.S.Pat. No. 6,432,974, Kelly et al., Aug. 13, 2002, intermediate 2) wasadded ethanol (8 mL) and 21% sodium ethoxide in ethanol (1.5 mL, 4 mmol)in a vial. The vial was flushed with argon and heated at 80° C.overnight with stirring. The reaction was quenched with 1M hydrogenchloride (8 mL) and diluted with water to give a precipitate. Theprecipitate was collected by vacuum filtration to give a yellow solid.The solid was dissolved in of dimethylformamide (3 mL) and purified byreverse phase chromatography with 45-75% acetonitrile/water to give(±)-3-(4-fluorophenyl)-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid as a 25/75 mixture of the cis/trans-diastereomers (290 mg, 0.68mmol, 63% yield). ES-MS m/z 430 (M+H).

Example 14

2-(6-cyanopyridin-3-yl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate

The title compound was prepared from ethyl6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 16; 0.300 g, 0.93 mmol) and 5-hydrazinylpicolinonitriledihydrochloride (Preparation 5; 535 mg, 1.9 mmol) according to Method Band Method C. The crude precipitate was purified by reverse phasechromatography with 40-80% acetonitrile/water to give the title compoundwhich was largely present as(±)-(3RS,3aRS)-2-(6-cyanopyridin-3-yl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate (yellow solid, 43 mg, 0.10 mmol, 11% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.91 (m, 1H), 1.74-1.87 (m, 1H),2.84-3.06 (m, 2H), 3.91-4.04 (m, 1H), 5.96 (d, J=11.01 Hz, 1H),6.82-7.59 (m, 5H), 7.76 (d, J=8.59 Hz, 1H), 7.79 (s, 1H), 7.84 (dd,J=8.32, 1.61 Hz, 1H), 8.14 (d, J=8.06 Hz, 1H), 8.45 (br. s., 1H),12.93-13.19 (m, 1H). ES-MS m/z 413 (M+H).

Example 15

2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid Step 1: Preparation of methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[o]indazole-7-carboxylate

Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 18, 2.8 g, 9.9 mmol) was suspended in ethanol (100 mL) and2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1, 2.6 g,12.8 mmol) was added. The solution was heated to 80° C. for eight hours.The solution was returned to ambient temperature. The resulting solidwas collected by vacuum filtration and washed with cold ethanol toprovide the title compound largely present as (±)-(3SR,3aRS)-methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate(3.75 g, 87% yield). LC/MS on 4.6×50 mm C-18 column, t_(R)=7.45 minutes(10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute withdetection 254 nm, at 50° C.); ES-MS m/z 434 (M+H); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.06-1.54 (m, 6H), 1.62-1.74 (m, 1H), 1.73-1.87 (m, 1H),1.99-2.09 (m, 1H), 2.21 (dd, J=7.79, 2.15 Hz, 1H), 2.82-2.94 (m, 2H),3.09 (d, J=16.92 Hz, 1H), 3.54-3.66 (m, 1H), 3.84 (s, 3H), 4.95 (dd,J=9.67, 5.64 Hz, 1H), 7.19 (dd, J=9.26, 1.75 Hz, 1H), 7.39 (d, J=2.15Hz, 1H),

Step 2: Preparation of2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

To a solution of the methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylatefrom step 1 (3.75 g, 8.6 mmol) in methanol (10 mL) and tetrahydrofuran(30 mL) was added 10% aqueous sodium hydroxide (10 mL). The solution wasstirred for 20 hours at ambient temperature. The resulting slurry wasconcentrated to half volume and acidified to a pH of about 2 with 1Mhydrochloric acid. The resulting solid was collected by vacuumfiltration to provide the title compound largely present as(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid (yellow solid, 3.79 g, quantitative yield). LC/MS on 4.6×50 mm C-18column, t_(R)=6.74 minutes (10 to 90% acetonitrile/water over 8 minutesat 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 420 (M+H);HRMS Calculated for C₂₄H₂₂ClN₃O₂: 420.1473 (M+H)⁺. Found: 420.1449; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.55 (m, 6H), 1.64-1.75 (m, 2H),1.75-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.15-2.23 (m, 1H), 2.78-2.91 (m,2H), 3.00 (d, J=16.11 Hz, 1H), 4.89 (dd, J=9.26, 5.77 Hz, 1H), 7.14 (dd,J=9.00, 1.75 Hz, 1H), 7.34 (d, J=1.88 Hz, 1H), 7.63 (d, J=8.86 Hz, 1H),7.73 (s, 1H), 7.76 (s, 1H), 7.94 (d, J=7.79 Hz, 1H).

Example 16

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 15 using chiral resolution (e.g., Method G).

Example 17

(3R,3aS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 15 using chiral resolution (e.g., Method G).

Example 18

2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 and 4-hydrazinylbenzonitrile hydrochloride (Aldrich)according to Method B and Method C. The title compound was largelypresent as(±)-(3SR,3aRS)-2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18-1.54 (m, 7H), 1.65-1.74 (m,1H), 1.77-1.89 (m, 1H), 2.04-2.12 (m, 1 H), 2.20-2.28 (m, 1H), 2.83-2.95(m, 1H), 3.05-3.14 (m, 1H), 3.55-3.63 (m, 1H), 4.91 (dd, J=9.53, 5.50Hz, 1H), 7.29 (d, J=8.86 Hz, 2H), 7.60 (d, J=8.86 Hz, 2H), 7.82 (dd,J=8.19, 1.48 Hz, 1H), 7.86 (s,

Example 19

(3S,3aR)-2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 18 using chitral resolution (e.g., Method G).

Example 20

(3R,3aS)-2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 18 using chitral resolution (e.g., Method G).

Example 21

2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 (310.5 mg, 1.09 mmol) and4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 (265 mg,1.45 mmol) according to Method B and Method C (hydrolysis conducted at60° C.). The crude precipitate was purified by reverse phasechromatography with 60-95% acetonitrile/water to give the title compound(yellow solid, 280 mg, 0.563 mmol, 64% yield). The title compound waslargely present as(±)-(3SR,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.56 (m, 7H), 1.64-1.74 (m,1H), 1.76-1.92 (m, J=12.89, 4.30 Hz, 1H), 2.01-2.14 (m, 1H), 2.18-2.29(m, 1H), 2.41 (s, 3H), 2.81-2.96 (m, 1H), 3.04-3.14 (m, 1H), 3.51-3.63(m, 1H), 4.89 (dd, J=9.67, 5.37 Hz, 1H), 7.09 (dd, J=8.59, 2.15 Hz, 1H),7.22 (d, J=1.88 Hz, 1H), 7.52 (d, J=8.59 Hz, 1H), 7.82 (dd, J=8.19, 1.48Hz, 1H), 7.85 (s, 1H), 8.07 (d, J=8.06 Hz, 1H), 13.01 (s, 1H). ES-MS m/z400 (M+H).

Example 22

(3S,3aR)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from the2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 21 using chiral resolution (e.g., Method G(Chiralcel OJ-H 30×250 mm; 50% ethanol/carbon dioxide). First elutingpeak: chiral HPLC t_(R)=2.31 minutes (Chiralcel OJ-H 4.6×250 mm; 50%ethanol/carbon dioxide)).

Example 23

(3R,3aS)-2-(4-cyano-3-methyphenyl)-3-cyclopentyl-3,3a-4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from the2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 21 using chiral resolution (e.g., Method G(Chiralcel OJ-H 30×250 mm; 50% ethanol/carbon dioxide). Second elutingpeak: chiral HPLC t_(R)=3.49 minutes (Chiralcel OJ-H 4.6×250 mm; 50%ethanol/carbon dioxide)).

Example 24

2-(5-cyano-6-methylpyridin-2-yl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 and 6-hydrazinyl-2-methylnicotinonitrile; Preparation 6according to Method B and Method C. The tile compound was largelypresent as(±)-(3SR,3aRS)-2-(5-cyano-6-methylpyridin-2-yl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24-1.52 (m, 5H), 1.56-1.89 (m,5H), 2.11-2.19 (m, 1H), 2.22-2.28 (m, 1H), 2.85-2.95 (m, 1H), 3.55-3.63(m, 1H), 5.12 (dd, J=9.70, 5.67 Hz, 1H), 7.17 (d, J=8.78 Hz, 1H),7.74-7.85 (m, 2H), 7.87 (s, 1H), 8.08 (d, J=8.05 Hz, 1H). (Missed —CH₃due to DMSO overlap) HRMS m/z 401.1965 (M±H).

Example 25

2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 (310 mg, 1.09 mmol) and4-hydrazinyl-2-methoxybenzonitrile hydrochloride; Preparation 4 (282 mg,1.42 mmol) according to Method B (methanol was used in place of ethanolas solvent) and Method C. The crude precipitate was purified by reversephase chromatography with 40-95% acetonitrile/water to give the titlecompound (yellow solid, 220 mg, 0.53 mmol, 49% yield). The titlecompound was largely present as(±)-(3SR,3aRS)-2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (m, 7H), 1.65-1.90 (m, 2H),1.99-2.12 (m, 1H), 2.18-2.27 (m, 1H), 2.82-2.95 (m, 1H), 3.04-3.13 (m,1H), 3.52-3.63 (m, 1H), 3.90 (s, 3H), 4.94 (dd, J=9.67, 5.37 Hz, 1H),6.80 (dd, J=8.59, 1.88 Hz, 1H), 6.90 (d, J=1.61 Hz, 1H), 7.45 (d, J=8.59Hz, 1H), 7.81 (dd, J=8.19, 1.48

Example 26

(3S,3aR)-2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 25 using chiral resolution (e.g., Method G).

Example 27

(3R,3aS)-2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3.3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3.3a,4.5°tetrahydro-2H-benzo[g]indazole-7-carboxylic acid prepared in Example 25using chiral resolution (e.g., Method G).

Example 28

2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

A mixture of 4-hydrazinyl-2-(methoxymethyl)benzonitrile hydrochloride,Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 (209 mg, 0.73 mmol) and ethanol (4 mL) was stirred underargon at 80° C. for four hours. The mixture was cooled to roomtemperature and concentrated to give ethyl2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylateas a yellow solid. The ester was suspended in tetrahydrofuran (4 mL),methanol (1 mL) and treated with 2.5 N sodium hydroxide (1 mL) at roomtemperature. After four hours the mixture was concentrated to half theoriginal volume, treated with 6 N Hydrogen chloride (2 mL),dimethylsulfoxide (24 mL) and purified by reversed-phase HPLC(acetonitrile/water/0.05° A) trifluoroacetic acid) to give2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid (yellow/orange solid, 65 mg, 0.015 mmol, 18% yield). The titlecompound was largely present as(±)-(3RS,3aSR)-2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.04 (s, 1H), 8.07 (d, J=8.06 Hz,1H), 7.80-7.87 (m, 2H), 7.60 (d, J=8.86 Hz, 1H), 7.35 (d, J=2.15 Hz,1H), 7.18 (dd, J=8.86, 2.15 Hz, 1H), 4.92 (dd, J=9.80, 5.51 Hz, 1H),4.50 (s, 2H), 3.59 (ddd, J=13.83, 9.40, 4.70 Hz, 1H), 3.36 (s, 3H),3.06-3.15 (m, 1H), 2.82-2.96 (m, 1H), 2.19-2.29 (m, 1H), 2.00-2.13 (m,1H), 1.65-1.89 (m, 2H), 1.14-1.54 (m, 7H). ES-MS m/z 430 (M+H)

Example 29

2-(4-cyano-3-((dimethylamino)methyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate

A mixture of 2-((dimethylamino)methyl)-4-hydrazinylbenzonitiledihydrochloride; Preparation 11 (208 mg, 1.1 mmol), Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 (153 mg, 0.54 mmol), and ethanol (6 mL) was stirred underargon at 80° C. for four hours. The mixture was cooled to roomtemperature, concentrated and purified by reversed-phase HPLC(acetonitrile/water/0.05% trifluoroacetic acid) to give methyl2-(4-cyano-3-((dimethylamino)methyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate.The ester was dissolved in tetrahydrofuran (3 mL), methanol (1 mL) andtreated with 2.5 N sodium hydroxide (1 mL) at room temperature. Themixture was stirred for 90 minutes, concentrated and the crude productpurified by reversed-phase HPLC (acetonitrile/water/0.05%trifluoroacetic acid) to yield2-(4-cyano-3-((dimethylamino)methyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate (yellow solid, 104 mg, 0.18 mmol, 35% yield). Thetitle compound was largely present as (±)-(3RS,3aSR)-2-(4-cyano-3-((dimethylamino)methyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.06 (s, 1H),8.08 (d, J=8.06 Hz, 1H), 7.82-7.91 (m, 2H), 7.72 (d, J=8.59 Hz, 1H),7.61 (s, 1H), 7.30 (d, J=8.32 Hz, 1H), 4.92 (dd, J=9.53, 5.50 Hz, 1H),4.28-4.47 (m, 2H), 3.62 (ddd, J=13.56, 9.26, 4.83 Hz, 1H), 3.12 (d,J=16.11 Hz, 1H), 2.89-2.97 (m, 1H), 2.84 (s, 6H), 2.22-2.30 (m, 1H),2.04-2.16 (m, 1H), 1.85 (ddd, J=25.91, 13.02, 3.49 Hz, 1H), 1.72 (s,1H), 1.15-1.56 (m, 7H). ES-MS m/z 443 (M+H).

Example 30

methyl2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

A mixture of 2-(benzyloxy)-4-hydrazinylbenzonitrile; Preparation 13 (358mg, 1.5 mmol), Methyl6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 18 (284 mg, 1.0 mmol), ethanol (7 mL), and 1 drop ofconcentrated hydrogen chloride was stirred under argon at 80° C. for 64hours. The mixture was cooled to room temperature, concentrated andpurified by normal phase flash column chromatography on a 40 g silicagel column (20-80% ethyl acetate/hexanes gradient). Pure fractions werepooled and concentrated in vacuo to yield methyl2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate(yellow foam, 485 mg, 0.96 mmol, 96% yield). The title compound waslargely present as (±)-(3RS,3aSR)-methyl2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate.NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.51 (m, 7H), 1.56-1.68 (m, 1H), 1.82(ddd, J=25.85, 12.96, 3.89 Hz, 1H), 1.95-2.08 (m, 1H), 2.15-2.31 (m,1H), 2.82-2.95 (m, 1H), 3.11 (d, J=16.38 Hz, 1H), 3.53-3.63 (m, 1H),3.87 (s, 3H), 4.91 (dd, J=9.53, 5.50 Hz, 1H), 5.31 (q, J=12.35 Hz, 2H),6.85 (d, J=8.32 Hz, 1H), 6.96 (s, 1H), 7.35 (t, J=7.25 Hz, 1H),7.39-7.57 (m, 5H), 7.80-7.92 (m, 2H), 8.10 (d, J=8.32 Hz, 1H). ES-MS m/z506 (M÷H).

Example 31

2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

A mixture of methyl2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate,Example 30, (100 mg, 0.20 mmol), tetrahydrofuran (3 mL), and methanol (1mL) was treated with 2.5 N sodium hydroxide (1 mL) at room temperature.After 18 hours the mixture was concentrated to one-third of its originalvolume, diluted with water (3 mL) and treated with 2 N hydrogen chloride(2 mL). The mixture was extracted three times with ethyl acetate, driedover magnesium sulfate, filtered and concentrated to give2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid (yellow/orange solid, 90 mg, 0.18 mmol, 93% yield). The titlecompound was largely present as(±)-(3RS,3aSR)-2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMS (J-d₆) δ ppm 1.03-1.51 (m, 7H), 1.57-1.69 (m,1H), 1.74-1.89 (m, 1H), 1.95-2.07 (m, 1H), 2.18-2.29 (m, 1 H), 2.82-2.96(m, 1H), 3.03-3.14 (m, 1H), 3.57 (ddd, J=13.70, 9.40, 4.30 Hz, 1H), 4.91(dd, J=9.53, 5.50 Hz, 1H), 5.31 (g, J=12.35 Hz, 2H), 6.84 (d, J=8.86 Hz,1H), 6.96 (s, 1H), 7.35 (t, J=7.25 Hz, 1H), 7.40-7.53 (m, 5H), 7.81-7.88(m, 2H), 8.09 (d, J=8.06 Hz, 1H), 13.03 (s, 1H). ES-MS m/z 492 (M+H).

Example 32

methyl2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

A mixture of methyl2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate,Example 30, (345 mg, 0.68 mmol), catalytic 10% palladium on carbon, andethyl acetate was hydrogenated at 30 psi hydrogen for three hours. Themixture was filtered through Celite and concentrated. The solid wassuspended in diethyl ether/hexanes, a small amount of methanol andfiltered to give methyl2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate(150 mg, 0.36 mmol, 53% yield). The title compound was largely presentas (±)-(3RS,3aSR)-methyl2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.58 (m, 7H), 1.60-1.90 (m, 2H),2.06 (s, 1H), 2.16-2.30 (m, 1H), 2.79-2.95 (m, 1H), 3.05-3.15 (m, 1H),3.58 (ddd, J=13.76, 9.47, 4.70 Hz, 1H), 3.86 (s, 3H), 4.77 (dd, J=9.67,5.37 Hz, 1H), 6.70 (d, J=8.59 Hz, 1H), 6.82 (s, 1H), 7.36 (d, J=8.86 Hz,1H), 7.82-7.93 (m, 2H), 8.02 (d, J=8.06 Hz, 1H), 10.70 (s, 1H). ES-MSm/z 416 (M+H).

Example 33

methyl2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

A mixture of2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid (Example 31; 70 mg, 0.14 mmol), ethyl acetate, tetrahydrofuran, andmethanol was treated with 10% palladium on carbon (10 mg) andhydrogenated for four hours at 30 psi hydrogen. The mixture was filteredthrough Celite, and concentrated to give methyl2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate(57 mg, 0.14 mmol) as a yellow solid. The title compound was largelypresent as (±)-(3RS,3aSR)-methyl2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.58 (m, 8H), 1.61-1.75 (m, 1H),1.74-1.90 (m, 1H), 2.00-2.12 (m, 1H), 2.16-2.30 (m, 1H), 2.79-2.96 (m,1H), 3.09 (d, J=16.11 Hz, 1H), 3.57 (ddd, J=13.76, 9.47, 4.70 Hz, 1H),4.76 (dd, J=9.67, 5.37 Hz, 1H), 6.69 (dd, J=8.86, 1.61 Hz, 1H), 6.82 (s,1H), 7.36 (d, J=8.59 Hz, 1H), 7.82-7.90 (m, 2H), 8.00 (d, J=8.06 Hz,1H), 10.70 (s, 1H). ES-MS m/z 402 (M+H).

Example 34

2-(3-chloro-4-cyanophenyl)-3-((R)-tetrahydrofuran-3-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid and2-(3-chloro-4-cyanophenyl)-3-((S)-tetrahydrofuran-3-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compounds were prepared according to Method B and Method Cfrom (±)-methyl5-oxo-6-((tetrahydrofuran-3-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate(Preparation 20) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride(Preparation 1), yielding a yellow solid (167 mg, quantitative yield).The title compounds were largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-((R)-tetrahydrofuran-3-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid and(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-((S)-tetrahydrofuran-3-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, respectively. LC/MS on 4.6×50 mm C-18 column, t_(R)=4.93 minutes(10 to 90% acetonitrile/water over 6 minutes at 2 mL/minute withdetection 254 nm, at 50° C.); ES-MS m/z 422 (M±H); HRMS

Calculated for C₂₃H₂₀ClN₃O₃: 422.1266 (M+H)⁺. Found: 422.1257; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.51-1.99 (m, 3H) 2.11-2.27 (m, 1H) 2.91 (dd,J=12.35, 4.03 Hz, 1H) 3.03-3.13 (m, 1H) 3.38-3.47 (m, 1H) 3.49-3.57 (m,1H) 3.58-3.69 (m, 1H) 3.73 (t, J=8.06 Hz, 1H) 3.77-3.85 (m, 1H)4.75-4.83 (m, 1H) 4.99 (dd, J=9.40, 6.71 Hz, 1H) 7.18 (td, J=8.59, 2.15Hz, 1H) 7.39 (dd, J=18.80, 2.15 Hz, 1H) 7.69 (dd, J=8.86, 5.10 Hz, 1H)7.80 (d, J=8.06 Hz, 1H) 7.84 (s, 1H) 8.08 (d, J=8.32 Hz, 1H) 13.07 (br.s., 1H).

Example 35

2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared according to Method B and Method C frommethyl6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 19 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride(Preparation 1) to give2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid (150 mg, 0.36 mmol, 65% yield) as a yellow solid. The titlecompound was largely present as(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.77 (m, 4H), 1.77-1.98 (m,3H), 2.07-2.18 (m, 1H), 2.51-2.59 (m, 1H), 2.80-2.93 (m, 1 H), 2.97-3.07(m, 1H), 3.44-3.56 (m, 1H), 4.88 (dd, J=9.40, 6.98 Hz, 1H), 7.22 (dd,J=8.86, 1.88 Hz, 1 H), 7.42 (d, J=2.15 Hz, 1H), 7.67 (d, J=8.86 Hz, 1H),7.75-7.83 (m, 2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 420 (M+H)

Example 36

2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl5-oxo-6-((tetrahydro-2H-pyran-4-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 21, and 2-chloro-4-hydrazinylbenzonitrile hydrochloride(Preparation 1) according to Method B and Method C. The title compoundwas largely present as(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24-1.33 (m, 2H), 1.40 (ddd,J=24.57, 12.08, 4.70 Hz, 1H), 1.50-1.57 (m, 1H), 1.86-1.99 (m, 2H),2.25-2.32 (m, 1H), 2.85-2.95 (m, 1H), 3.07-3.20 (m, 3H), 3.61-3.79 (m,3H), 4.83 (dd, J=9.67, 3.76 Hz, 1H), 7.21 (d, J=8.86 Hz, 1H), 7.44 (d,J=1.61 Hz, 1H), 7.71 (d, J=8.59 Hz, 1H), 7.83 (dd, J=8.32, 1.34 Hz, 1H),7.87 (s, 1H), 8.09 (d, J=8.32 Hz, 1H), 13.07 (s, 1H); HRMS m/z 436.1445(M+H).

Example 37

2-(4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl5-oxo-6-((tetrahydro-2H-pyran-4-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 21 and 4-hydrazinylbenzonitrile hydrochloride (Aldrich)according to Method B and Method C. The title compound was largelypresent as(±)-(3SR,3aRS)-2-(4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.33(m, 2H), 1.41 (ddd, J=24.64, 12.29, 4.43 Hz, 1H), 1.48-1.55 (m, 1H),1.87-1.99 (m, 2H), 2.25-2.33 (m, 1H), 2.84-2.95 (m, 1H), 3.07-3.20 (m,3H), 3.57-3.68 (m, 1H), 3.68-3.78 (m, 2H), 4.78 (dd, J=9.94, 3.49 Hz,1H), 7.30 (d, J=8.86 Hz, 2H), 7.63 (d, J=8.86 Hz, 2H), 7.82 (dd, J=8.19,1.48 Hz, 1H), 7.86 (s, 1H), 8.05 (d, J=8.06 Hz, 1H), 13.03 (br. s., 1H);HAMS m/z 402.1838 (M+H).

Example 38

2-(3-chloro-4-cyanophenyl)-3-(piperidin-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate

The title compound was prepared from tert-butyl4-((6-(methoxycarbonyl)-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)piperidine-1-carboxylate;Preparation 22 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride(Preparation 1) according to Method B and Method C. The title compoundwas largely present as(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(piperidin-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid trifluoroacetate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.60 (m,3H), 1.91-1.99 (m, 2H), 2.07-2.14 (m, 1H), 2.80-2.96 (m, 2H), 3.03-3.09(m, 2H), 3.22-3.28 (m, 1H), 3.32-3.41 (m, 3H), 4.35 (dd, J=8.06, 4.03Hz, 1H), 7.24 (dd, J=8.86, 2.15 Hz, 1H), 7.41 (d, J=2.15 Hz, 1H), 7.78(d, J=8.86 Hz, 1H), 7.82 (dd, J=8.32, 1.34 Hz, 1H), 7.84 (s, 1H), 7.91(d, J=8.06 Hz, 1H), 8.08-8.18 (m, 1H), 8.52-8.59 (m, 1H), 13.10 (br. s.,1H); HRMS m/z 435.1589 (M+H).

Example 39

2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(5-methyl-2-furylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 23 (444 mg, 1.5 mmol) and 2-chloro-4-hydrazinylbenzonitrilehydrochloride; Preparation 1 (303 mg, 1.5 mmol) according to Method Band Method C. The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.27 (m, 1H), 1.93 (dt,J=8.11, 4.35 Hz, 1H), 2.10 (s, 3H), 2.99 (d, J=5.47 Hz, 2H), 3.90 (td,J=12.21, 4.88 Hz, 1H), 5.93 (d, J=10.94 Hz, 1H), 5.97 (d, J=2.34 Hz,1H), 6.30 (d, J=3.12 Hz, 1H), 7.10 (br. s., 1H) 7.35 (br. s., 1H), 7.70(d, J=8.59 Hz, 1H), 7.83-7.86 (m, 2H), 8.12 (d, J=8.59 Hz, 1H) 13.07 (s,1H). ES-MS m/z 432 (M+H).

Example 40

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 39 using chiral resolution (e.g., Method G).ES-MS m/z 432 (M+H).

Example 41

(3S,3aS)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 39, according to Method G.

Example 42

2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(cyclopent-1-en-1-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 24 (268 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrilehydrochloride; Preparation 1 (303 mg, 1.5 mmol) according to Method Band Method C. The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (dd, J=13.09, 5.67 Hz, 1H),1.73 (dt, J=17.59, 6.64 Hz, 2H), 1.85 (m, 1H), 1.90-2.00 (m, 1H), 2.07(s, 1H), 2.10 (dt, J=5.86, 3.71 Hz, 1H), 2.22 (br. s., 2H), 2.99-3.06(m, 2H), 3.71-3.77 (m, 1H), 5.48 (d, J=10.55 Hz, 1H), 5.69 (br. s., 1H),7.72 (d, J=8.60 Hz, 1H), 7.83 (d, J=8.21 Hz, 1H), 7.85 (s, 1H), 8.09 (d,J=8.21 Hz, 1H); ES-MS m/z 418 (M+H).

Example 43

2-(3-chloro-4-cyanophenyl)-3-(2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(2-furylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 25 (268 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrilehydrochloride; Preparation 1 (254 mg, 1.25 mmol) according to Method Band Method C. The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (br. s., 1H), 1.94 (d, J=4.10Hz, 1H), 2.98 (br. s., 2H), 3.93 (td, J=12.06, 4.98 Hz, 1H), 6.02 (d,J=10.74 Hz, 1H), 6.38 (dd, J=3.22, 1.86 Hz, 1H), 6.46 (d, J=3.12 Hz,1H), 7.11 (br. s., 1H), 7.35 (br. s., 1H), 7.53 (d, J=0.98 Hz, 1H), 7.70(d, J=8.79 Hz, 1H), 7.83-7.85 (m, 2H), 8.12 (d, J=8.20 Hz, 1H); ES-MSm/z 418 (M+H).

Example 44

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[d]indazole-7-carboxylicacid prepared in Example 43 using chiral resolution (e.g., Method G).ES-MS m/z 418 (M+H).

Example 45

(3S,3aS)-2-(3-chloro-4-cyanophenyl)-3-(2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 43 using chiral resolution (e.g., Method G).

Example 46

2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(3-furylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate,Preparation 26 (268 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrilehydrochloride; Preparation 1 (254 mg, 1.25 mmol) according to Method Band Method C. The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (br. s., 1H), 1.91 (d, J=5.08Hz, 1H), 3.00 (d, J=2.73 HZ, 2H), 3.85 (ddd, J=13.38, 10.64, 4.88 Hz, 1H), 5.89 (d, J=10.94 Hz, 1H), 6.08 (s, 1H), 7.05 (br. s., 1H), 7.32 (br.s., 1H), 7.56 (s, 1H), 7.63 (s, 1H), 7.69 (d, J=8.59 Hz, 1H), 7.82-7.89(m, 2H), 8.13 (d, J=8.20 Hz, 1H), 13.06 (br. s., 1H); ES-MS m/z 418(M+H).

Example 47

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 46 using chiral resolution (e.g., Method G).ES-MS m/z 418 (M+H).

Example 48

(3S,3aS)-2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound is prepared from the2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid prepared in Example 46 using chiral resolution (e.g., Method G).

Example 49

2-(3-chloro-4-cyanophenyl)-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-[(2-methyl-1,3-thiazol-5-yl)methylene]-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 27 (469 mg, 1.5 mmol) and 2-chloro-4-hydrazinylbenzonitrilehydrochloride; Preparation 1 (303 mg, 1.5 mmol) according to Method Band Method C. The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (s, 1H), 1.94 (dt, J=7.91,4.44 Hz, 1H), 2.50 (s, 3H), 2.99 (d, J=5.47 Hz, 2H), 3.95 (br. s., 1H),6.32 (d, J=10.55 Hz, 1H), 7.11 (br. s., 1H), 7.38 (br. s., 1H), 7.64 (s,1H), 7.72 (d, J=8.59 Hz, 1H), 7.82-7.87 (m, 2H), 8.15 (d, J=8.20 Hz,1H); ES-MS m/z 449 (M+H).

Example 50

2-(4-cyanophenyl)-3-cyclopent-1-en-1-yl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(cyclopent-1-en-1-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 24 (268 mg, 1.0 mmol) and 4-hydrazinylbenzonitrilehydrochloride (Aldrich; 254 mg, 1.5 mmol) according to Method B andMethod C.

The title compound was largely present as(±)-(3RS,3aRS)-2-(4-cyanophenyl)-3-cyclopent-1-en-1-yl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (dd, J=13.28, 5.47 Hz, 1H),1.66 (dt, J=7.32, 3.96 Hz, 1H), 1.75 (d, J=5.47 Hz, 1H), 1.79 (br. s.,1H), 1.97 (br. s., 1H), 2.10 (dd, J=8.79, 3.71 Hz, 1H), 2.21 (br. s.,2H), 2.98-3.04 (m, 2H), 3.67-3.74 (m, −1H), 5.44 (d, J=10.55 Hz, 1H),5.65 (s, 1H), 7.16 (br. s., 2H), 7.63 (d, J=8.98 Hz, 2H), 7.81-7.85 (m,2H), 8.05 (d, J=8.20 Hz, 1H); ES-MS m/z 384 (M+H).

Example 51

2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(cyclopent-1-en-1-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 24 and 4-hydrazinyl-2-methylbenzonitrile hydrochloride;Preparation 2 according to Method B and Method C. The title compound waslargely present as(±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.85 (m, 4H), 1.88-2.12 (m,2H), 2.18 (s, 2 H), 2.38 (s, 3H), 2.99 (d, J=4.0 Hz, 2H), 3.55-3.75 (m,1H), 5.39 (d, J=10.7 Hz, 1H), 5.62 (s, 1H), 6.86 (br. s., 1H), 7.13 (br.s., 1H), 7.52 (d, J=8.6 Hz, 1H), 7.69-7.89 (m, 2H), 8.03 (d, J=7.8 Hz,1H), 12.99

Example 52

2-(4-cyanophenyl)-3-isoxazol-5-yl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

The title compound was prepared from methyl6-(isoxazol-5-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate;Preparation 28 (268 mg, 1.0 mmol) and 4-hydrazinylbenzonitrilehydrochloride (Aldrich; 254 mg, 1.5 mmol) according to Method B andMethod C. The title compound was largely present as(±)-(3RS,3aRS)-2-(4-cyanophenyl)-3-isoxazol-5-yl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.26 (m, 1H), 1.97 (d,J=13.67 Hz, 1H), 2.99 (dd, J=6.64, 2.73 Hz, 1H), 4.06 (d, J=4.69 Hz,1H), 6.12 (d, J=11.33 Hz, 1H), 6.28 (s, 1H), 7.12 (d, J=7.42 Hz, 2H),7.63 (d, J=8.98 Hz, 2H), 7.82-7.86 (m, 3H), 8.09 (d, J=8.20 Hz, 1H),8.84 (s, 1H), 13.05 (s, 1H); ES-MS m/z 385 (M+H).

Example 53

(±)-(3SR,3aSR)-2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 and4-hydrazinyl-2-methylbenzonitrile hydrochloride (Preparation 2)according to Method B and Method C (yellow solid, 32 mg, 0.07 mmol, 15%yield). The title compound was largely present as(±)-(3SR,3aSR)-2-(4-cyano-3-methylphenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.37 (s, 3H), 3.16 (dd, J=12.49,10.61 Hz, 1H), 4.19-4.31 (m, 1H), 4.39 (dd, J=10.47, 5.91 Hz, 1H), 5.95(d, J=11.28 Hz, 1H), 6.94-6.98 (m, 6H), 7.40 (d, J=1.07 Hz, 1H), 7.50(d, J=8.59 Hz, 1H), 7.61 (dd, J=8.32, 1.34 Hz, 1H), 7.99 (d, J=8.32 Hz,1H), 13.17 (s, 1H). ES-MS m/z 428 (M+H).

Example 54

2-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 (155mg, 0.50 mmol) and (178 mg, 0.75 mmol) according to Method B and MethodC. The crude product was purified by reverse-phase HPLC(acetonitrile/water/0.05% trifluoroacetic acid) to give2-(4-cyano-3-trifluoromethyl)phenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (58 mg, 0.12 mmol, 24% yield). The title compound was largelypresent as(±)-(3SR,3aSR)-2-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.22 (t, J=11.82 Hz, 1H),4.24-4.37 (m, 1H), 4.40 (dd, J=10.07, 5.77 Hz, 1H), 6.08 (d, J=11.01 Hz,1H), 7.18 (s, 6H), 7.41 (s, 1H), 7.61 (d, J=8.32 Hz, 1H), 7.85 (d,J=8.86 Hz, 1H), 8.05 (d, J=8.06 Hz, 1H), 13.23 (s, 1H). ES-MS m/z 482(M+H).

Example 55

2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 (155mg, 0.50 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride;Preparation 1 (153 mg, 0.75 mmol) according to Method B and Method C.The crude product was purified by reverse-phase HPLC(acetonitrile/water/0.05% trifluoroacetic acid) to give2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (41 mg, 0.09 mmol, 18% yield). The title compound was largelypresent as(±)-(3SR,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ES-MS m/z 448 (M+H).

Example 56

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from the2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 55 using chiral resolution (e.g., Method G).

Example 57

(3S,3aS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from the2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 55 using chiral resolution (e.g., Method G).

Example 58

2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 (155mg, 0.50 mmol) and 4-hydrazinylbenzonitrile hydrochloride (Aldrich) (127mg, 0.75 mmol) according to Method B and Method C. The crude product waspurified by reverse-phase HPLC (acetonitrile/water/0.05c/0trifluoroacetic acid) to give2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (52 mg, 0.13, 25% yield). The title compound was largely present as(±)-(3SR,3aSR)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) ppm 3.17 (dd, J=12.89, 10.47 Hz, 1H),4.19-4.32 (m, 1H), 4.39 (dd, J=10.47, 5.91 Hz, 1H), 5.97 (d, J=11.55 Hz,1H), 6.93-7.27 (m, 6H), 7.40 (d, J=1.61 Hz, 1H), 7.57-7.63 (m, 3H), 7.99(d, J=8.06 Hz, 1H), 13.18 (s, 1 H). ES-MS m/z 414 (M+H).

Example 59

(3R,3aR)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 58 using chiral resolution (e.g., Method H).

Example 60

(3S,3aS)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 58 using chiral resolution (e.g., Method G).

Example 61

2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate; Preparation 31 and4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 accordingto Method B and Method C (yellow solid, 301 mg, 0.751 mmol, 75% yield).The title compound was largely present as(±)-(3RS,3aSR)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.15 (s, 1 H), 7.94 (d, J=8.2 Hz,1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.46 (d,J=1.6 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.08 (dd, J=8.8, 2.1 Hz, 1H),4.89 (dd, J=9.8, 7.0 Hz, 1H), 4.78 (dd, J=10.2, 5.9 Hz, 1H), 4.30 (dd,J=12.9, 10.5 Hz, 1H), 3.97 (ddd, J=13.0, 9.9, 5.7 Hz, 1H), 2.41 (s, 3H),2.01-2.16 (m, 1H), 1.13-1.67 (m, 8H). ES-MS m/z 402 (M+H).

Example 62

(3S,3aR)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from the2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 61 using chiral resolution (e.g., Method G(Chiralcel OJ-H 30×250 mm; 60% methanol/carbon dioxide). First elutingpeak: t_(R)=3.29 minutes (Chiralcel OJ-H 4.6×250 mm; 50% methanol/carbondioxide).

Example 63

(3R,3aS)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from the2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 61 using chiral resolution (e.g., Method G(Chiralcel OJ-H 30×250 mm; 60% methanol/carbon dioxide). Second elutingpeak: t_(R)=5.83 minutes (Chiralcel OJ-H 4.6×250 mm; 50% methanol/carbondioxide).

Example 64

2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate, Preparation 31 (573mg, 2.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride;Preparation 1 (612 mg, 3.0 mmol) according to Method B and Method C. Thecrude precipitate was formed from dimethylformamide and methanol to give2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (yellow solid, 237 mg, 0.563 mmol, 28% yield). The title compoundwas largely present as(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.20 (s, 1 H), 7.98 (d, J=8.2 Hz,1H), 7.70 (d, J=9.0 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (d,J=1.2 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.8, 2.1 Hz, 1H),4.95 (dd, J=9.4, 7.0 Hz, 1H), 4.78 (dd, J=10.2, 5.9 Hz, 1H), 4.31 (dd,J=13.3, 10.5 Hz, 1H), 4.00 (ddd, J=13.2, 9.7, 5.7 Hz, 1H), 2.03-2.16 (m,1H), 1.13-1.68 (m, 8H). ES-MS m/z 422 (M+H).

Example 65

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from the2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 64 using chiral resolution (e.g., Method G).

Example 66

(3R,3aS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from the2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 64 using chiral resolution (e.g., Method G).

Example 67

2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared by epimerization of2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid, Example 64 (131 mg) in a solution of 0.5 M sodiummethoxide/methanol (4 mL) and tetrahydrofuran (2 mL) at 50° C. After 24hours, the reaction was concentrated under a stream of nitrogen andpurified by reverse-phase HPLC (60 to 90% acetonitrile/water/0.05%trifluoroacetic acid) to give2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (yellow solid, 26.7 mg, 0.0634 mmol, 20% yield). The title compoundwas largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (br. s., 1H), 7.82 (d, J=8.2Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.56 (dd, J=7.8, 1.6 Hz, 1H), 7.43 (d,J=1.6 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.18 (dd, J=9.0, 2.3 Hz, 1H),4.63 (dd, J=10.5, 5.9 Hz, 1H), 4.52 (dd, J=8.2, 4.7 Hz, 1H), 4.26 (dd,J=12.5, 10.5 Hz, 1H), 3.54-3.62 (m, 1H), 2.68-2.85 (m, 1H), 1.79-1.91(m, 1H), 1.20-1.71 (m, 7H). ES-MS m/z 422 (M+H).

Examples 68 and 69, Respectively

2-[4-cyano-3-(trifluoromethyl)phenyl]-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate (Preparation 31; 286mg, 1.0 mmol) and 4-hydrazinyl-2-(trifluoromethyl)benzonitrilehydrochloride (Preparation 3; 298 mg, 1.3 mmol) according to Method Band Method C. The title compound was largely present as a mixture of cisand trans diastereomers:

The crude product was purified by reverse-phase HPLC (60 to 95%acetonitrile/water/0.05% trifluoroacetic acid) to give(±)-(3RS,3aSR)-2-[4-cyano-3-(trifluoromethyl)phenyl]-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid, the first eluting diastereomer (cis) (yellow solid, 16.8 mg,0.0369 mmol, 3.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.22 (br. s.,1H), 7.99 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.57-7.62 (m, 2H),7.47 (d, J=1.6 Hz, 1H), 7.44 (dd, J=8.8, 1.8 Hz, 1 H), 5.04 (dd, J=9.8,7.0 Hz, 1H), 4.79 (dd, J=10.5, 5.9 Hz, 1H), 4.33 (dd, J=13.3, 10.5 Hz,1H), 4.03 (ddd, J=13.3, 9.4, 5.9 Hz, 1H), 2.04-2.17 (m, 1H), 1.59-1.69(m, 1H), 1.29-1.58 (m, 5H), 1.13-1.29 (m, 2H). ES-MS m/z 456 (M+H). Thesecond eluting diastereomer (trans),(±)-(3RS,3aRS)-2-[4-cyano-3-(trifluoromethyl)phenyl]-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (yellow solid, 29 mg, 0.0637 mmol, 6.4% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.18 (br. s., 1H), 7.93 (d, J=9.0 Hz, 1H), 7.84 (d,J=7.8 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.2, 1.6 Hz, 1H),7.44 (d, J=1.6 Hz, 1H), 7.39 (dd, J=8.8, 2.1 Hz, 1H), 4.65 (dd, J=10.4,5.7 Hz, 1H), 4.59 (dd, J=8.4, 4.5 Hz, 1H), 4.27 (dd, J=12.5, 10.5 Hz,1H), 3.61 (ddd, J=13.0, 7.7, 5.9 Hz, 1H), 2.69-2.82 (m, 1H), 1.79-1.91(m, 1H), 1.19-1.72 (m, 7H). ES-MS m/z 456 (M+H).

Example 70

2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate; Preparation 31 (286mg, 1.0 mmol) and 4-hydrazinylbenzonitrile hydrochloride (Aldrich; 254mg, 1.5 mmol) according to Method B and Method C.2-(4-Cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid was obtained (yellow solid, 142 mg, 0.367 mmol, 37% yield). Thetitle compound was largely present as(±)-(3RS,3aSR)-2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (br. s., 1H), 7.93 (d, J=7.8Hz, 1H), 7.53-7.66 (m, 3H), 7.46 (s, 1H), 7.27 (d, J=9.0 Hz, 2H), 4.90(dd, J=9.4, 7.0 Hz, 1H), 4.77 (dd, J=10.4, 5.7 Hz, 1H), 4.30 (dd,J=12.7, 10.7 Hz, 1H), 3.98 (ddd, J=12.9, 9.8, 5.9 Hz, 1H), 2.02-2.16 (m,1H), 1.56-1.67 (m, 1H), 1.43-1.55 (m, 3H), 1.29-1.43 (m, 2 H), 1.13-1.29(m, 2H). ES-MS m/z 388 (M+H).

Example 71

(3S,3aR)-2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 70 using chiral resolution (e.g. Method G).

Example 72

(3R,3aS)-2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound is prepared from the2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid prepared in Example 70 using chiral resolution (e.g. Method G).

Example 73

2-(4-cyano-3-methylphenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(2-methylpropylidene)-4-oxochroman-7-carboxylate (Preparation 32; 260mg, 1.0 mmol) and 4-hydrazinyl-2-methylbenzonitrile hydrochloride(Preparation 2; 275 mg, 1.5 mmol) according to Method B and Method C(yellow solid, 196 mg, 0.523 mmol, 52% yield, approximately 7:1 mixtureof cis:trans diastereomers). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (br.s., 1H), 7.93 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.55 (d,J=8.6 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.09 (dd,J=8.6, 2.3 Hz, 1H), 4.76-4.86 (m, 2H), 4.42 (dd, J=13.1, 10.4 Hz, 1H),4.02 (ddd, J=13.2, 10.6, 5.9 Hz, 1H), 2.42 (s, 3H), 2.06-2.17 (m, 1H),0.83 (d, J=7.4 Hz, 3H), 0.81 (d, J=7.4 Hz, 3H). ES-MS m/z 376 (M+H).

Example 74

2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(2-methylpropylidene)-4-oxochroman-7-carboxylate; Preparation 32 (260mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride;Preparation 1 (306 mg, 1.5 mmol) according to Method B and Method C. Thecrude product was purified by reverse-phase HPLC (30 to 95%acetonitrile/water/0.05% trifluoroacetic acid) followed by flashchromatrography (0 to 20% methanol/ethyl acetate) to give2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (yellow solid, 18.4 mg). The title compound was largely present as(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 7.95 (d, J=7.8Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (d,J=1.2 Hz, 1 H), 7.42 (d, J=2.3 Hz, 1H), 7.19 (dd, J=9.0, 1.6 Hz, 1H),4.77-4.88 (m, 2H), 4.41 (dd, J=13.3, 10.5 Hz, 1H), 4.00-4.09 (m, 1H),2.04-2.16 (m, 1H), 0.83 (d, J=7.0 Hz, 3H), 0.82 (d, J=7.0 Hz, 3H).

Example 75

2-(4-cyano-3-methylphenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate (Preparation 33),and 4-hydrazinyl-2-methylbenzonitrile hydrochloride (Preparation 2)according to Method B and Method C. The crude product was purified byreverse-phase HPLC (65 to 85% acetonitrile/water/0.05% trifluoroaceticacid) to give the title compound (yellow solid, 23 mg). The titlecompound was largely present as(±)-(3RS,3aSR)-2-(4-cyano-3-methylphenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (br. s., 1H), 7.94 (d, J=7.8Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.47 (d,J=1.6 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.11 (dd, J=8.6, 2.0 Hz, 1H),4.84 (dd, J=10.5, 5.9 Hz, 1H), 4.45 (dd, J=12.9, 10.5 Hz, 1H), 4.31 (t,J=10.0 Hz, 1H), 3.89 (ddd, J=13.0, 9.9, 5.7 Hz, 1H), 2.42 (s, 3H),0.71-0.81 (m, 1H), 0.62-0.70 (m, 1H), 0.49-0.58 (m, 1H), 0.35-0.43 (m,1H), 0.17-0.24 (m, 1H). ES-MS m/z 374 (M+H).

Example 76

2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

The title compound was prepared from methyl3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate; Preparation 33 and2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 accordingto Method B and Method C. The crude product was purified byreverse-phase H PLC (65 to 85% acetonitrile/water/0.05% trifluoroaceticacid) to give2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (yellow solid, 14 mg). The title compound was largely present as(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.18 (br. s., 1H), 7.97 (d, J=8.2Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.59 (dd, J=8.2, 1.6 Hz, 1H), 7.48 (d,J=1.6 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.6, 1.6 Hz, 1H),4.84 (dd, J=10.5, 5.9 Hz, 1H), 4.46 (dd, J=12.9, 10.5 Hz, 1H), 4.39 (t,J=10.0 Hz, 1H), 3.93 (ddd, J=13.1, 10.2, 5.7 Hz, 1H), 0.74-0.85 (m, 1H),0.63-0.71 (m, 1H), 0.52-0.61 (m, 1H), 0.37-0.45 (m, 1H), 0.18-0.26 (m,1H).

Example 77

(±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid Step 1: Preparation of methyl2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate

To a suspension of methyl3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate; Preparation 34(260 mg, 0.92 mmol) in ethanol (7 mL) was added4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 (218 mg,1.2 mmol). The slurry was heated to 80° C. for eighteen hours. Thesolution was returned to ambient temperature and the resulting solid wascollected by vacuum filtration and washed with cold ethanol.Chromatography (normal phase, ethyl acetate/hexane) provided largely thecis isomer of methyl2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate(yellow solid, 125 mg, 33% yield). LC/MS on 4.6×50 mm C-18 column,t_(R)=6.98 minutes (10 to 90% acetonitrile/water over 8 minutes at 2mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 414 (M+H). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.63-1.83 (m, 2H), 2.05-2.11 (m, 2H), 2.14-2.20(m, 2 H), 2.39 (s, 3H), 3.83 (s, 3H), 3.88 (dd, J=13.02, 10.34 Hz, 1H),3.98-4.03 (m, 1H), 4.67 (dd, J=10.20, 5.64 Hz, 1H), 5.45 (d, J=11.01 Hz,1H), 5.60 (br. s., 1H), 6.86 (br. s., 1H), 7.11 (br. s., 1H), 7.44 (d,J=1.34 Hz, 1H), 7.53 (d, J=8.59 Hz, 1H), 7.58 (dd, J=8.06, 1.61 Hz, 1H),7.93 (d, J=8.06 Hz, 1H).

Step 2: Preparation of2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

To a solution of methyl2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate(125 mg, 0.30 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) wasadded 1M aqueous sodium hydroxide (2 mL). The solution was stirred for20 hours at ambient temperature. The resulting slurry was concentratedto half volume, acidified to pH=2 with 1M hydrochloric acid andcollected by vacuum filtration (yellow solid, 66 mg, 55% yield). Thetitle compound was largely present as(±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. Reversed-phase HPLC on 4.6×50 mm C-18 column, t_(R)=2.92 minutes(10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute withdetection 254 nm, at 20° C.); HRMS Calculated for C₂₄H₂₁N₃O₃: 400.1656(M+H)⁺. Found: 400.1678. ¹H NMR (400 MHz, 1H), 3.97-4.06 (m, 1H), 4.65(dd, J=10.20, 5.91 Hz, 1H), 5.44 (d, J=10.47 Hz, 1H), 5.60 (br. s., 1H),6.86 (br. s., 1H), 7.11 (br. s., 1H), 7.42 (d, J=1.34 Hz, 1H), 7.53 (d,J=8.59 Hz, 1H), 7.56 (dd, J=8.19, 1.48 Hz, 1H), 7.90 (d, J=8.06 Hz, 1H),13.12 (br. s., 1H).

Example 78

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid Step 1: Preparation of methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate

Methyl 3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate;Preparation 34 (310 mg, 1.1 mmol) was suspended into ethanol (5 mL) and2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (289 mg,1.4 mmol) was added. The solution was heated to 80° C. for eighteenhours. The solution was returned to ambient temperature and theresulting solid was collected by vacuum filtration and washed with coldethanol. Chromatography (normal phase, ethyl acetate/hexane) providedlargely the cis isomer of methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate(yellow solid, 190 mg, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.60-1.90 (m, 2H), 2.04-2.14 (m, 2H), 2.14-2.22 (m, 2H), 3.83 (s, 3H),3.89 (dd, J=12.76, 10.34 Hz, 1H), 4.01-4.11 (m, 1H), 4.68 (dd, J=10.47,6.18 Hz, 1H), 5.51 (d, J=9.67 Hz, 1H), 5.63 (br. s., 1H), 6.99 (br. s.,1H), 7.27 (br. s., 1H), 7.45 (d, J=1.61 Hz, 1H), 7.58 (dd, J=8.19, 1.75Hz, 1H), 7.71 (d, J=8.86 Hz, 1 H), 7.97 (d, J=8.06 Hz, 1H).

Step 2: Preparation of2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid

To a solution of methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate(190 mg, 0.44 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) wasadded 1M aqueous sodium hydroxide (2 mL). The solution was stirred for20 hours at ambient temperature. The resulting slurry was concentratedto half volume and acidified to pH=2 with 1M hydrochloric acid. Theresulting solid was collected by vacuum filtration. The solid wastreated with hot N,N-dimethylformamide and methanol to provide2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid (yellow solid, 40 mg, 22% yield). The title compound was largelypresent as3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid. Reversed-phase HPLC on 4.6×50 mm C-18 column, t_(R)=3.05 minutes(10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute withdetection 254 nm, at 20° C.); HAMS Calculated for C₂₃H_(is)ClN₃O₃:420.1109 (M+H)⁺. Found: 420.1127; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.59-1.89 (m, 2H), 2.03-2.14 (m, 2H), 2.14-2.23 (m, 2H), 3.89 (dd,J=13.02, 10.34 Hz, 1H), 4.05 (ddd, J=12.89, 10.74, 5.91 Hz, 1H), 4.67(dd, J=10.34, 5.77 Hz, 1H), 5.51 (d, J=11.01 Hz, 1H), 5.63 (br. s., 1H),7.00 (br. s., 1H) 7.29 (br. s., 1H), 7.43 (d, J=1.61 Hz, 1H), 7.56 (dd,J=8.19, 1.48 Hz, 1H), 7.71 (d, J=8.59 Hz, 1H), 7.94 (d, J=8.06 Hz, 1H),13.16 (br. s., 1H).

Example 79

(±)-(3RS,3aRS)-[2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazol-7-yl]aceticacid

The title compound was prepared fromethyl[3-(4-fluorobenzylidene)-4-oxo-3,4-dihydro-2H-chromen-7-yl]acetate;Preparation 29 (170 mg, 0.5 mmol) and 4-hydrazinylbenzonitrilehydrochloride (Aldrich; 85 mg, 0.5 mmol)according to Method B and MethodC. The title compound was largely present as(±)-(3RS,3aRS)-[2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazol-7-yl]aceticacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.12 (dd, J=12.89, 10.55 Hz, 1H),3.56 (s, 2H), 4.12-4.25 (m, 1H), 4.34 (dd, J=10.16, 5.86 Hz, 1H), 5.90(d, J=10.94 Hz, 1H), 6.85 (s, 1H), 6.97 (d, J=8.2) Hz, 1H), 7.04 (s,3H), 7.15 (br. s., 3H), 7.57 (d, J=9.37 Hz, 2H), 7.82 (d, J=7.81 Hz,1H); ES-MS m/z 428 (M+H).

Example 80

3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile

The title compound was prepared from(E)-2-(4-fluorobenzylidene)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one(Yoshihama et al. U.S. Pat. No. 6,080,781; Example 80) and4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 accordingto Method B (off-white solid, 263 mg, 0.662 mmol, 66% yield, 20:1mixture of cis:trans diastereomers). The title compound was largelypresent as4-((3RS,3aRS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73 (qd, J=12.50, 3.91 Hz, 1H),1.68-1.80 (m, 1H), 2.33 (s, 3H), 2.64-2.75 (m, 1H), 2.76-2.93 (m, 1H),3.78 (ddd, J=13.09, 10.74, 5.08 Hz, 1H), 5.73 (d, J=10.94 Hz, 1 H), 6.57(d, J=2.34 Hz, 1H), 6.72 (dd, J=8.40, 2.54 Hz, 1H), 6.79-7.35 (m, 6H),7.42 (d, J=8.59 Hz, 1 H), 7.85 (d, J=8.59 Hz, 1H), 9.87 (s, 1H). ES-MSm/z 398 (M+H).

Example 81

4-((3R,3aR)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile

The title compound is prepared from the3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrileprepared in Example 80 using chiral resolution, according to Method G.

Example 82

4-((3S,3aS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile

The title compound is prepared from the3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrileprepared in Example 80 using chiral resolution, according to Method G.

Example 83

3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile

The title compound was prepared from(E)-2-(4-fluorobenzylidene)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one(Yoshihama et al. U.S. Pat. No. 6,080,781; Example 11) and4-hydrazinyl-2-(trifluoromethyl)benzonitrile hydrochloride; Preparation3 according to Method B (off-white solid, 342 mg).

The title compound was largely present as(±)-4-((3RS,3aRS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77 (dq, J=13.02, 4.69 Hz, 1H),1.65-1.82 (m, 1H), 2.65-2.76 (m, 1H), 2.78-2.94 (m, 1H), 3.86 (ddd,J=13.67, 11.33, 5.08 Hz, 1H), 5.87 (d, J=10.55 Hz, 1H), 6.59 (d, J=2.34Hz, 1H), 6.74 (dd, J=8.59, 2.34 Hz, 1H), 6.76-7.70 (m, 6H), 7.69-7.84(m, 1H), 7.89 (d, J=8.59 Hz, 1H), 9.96 (s, 1H). ES-MS m/z 452 (M+H).

Example 84

4-((3R,3aR)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile

The title compound is prepared from the3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrileprepared in Example 83 using chiral resolution (e.g., Method G).

Example 85

4-((3S,3aS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile

The title compound is prepared from the3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrileprepared in Example 83 using chiral resolution (e.g., Method G).

Example 86

2-chloro-4-(−3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile

The title compound was prepared from(E)-2-(4-fluorobenzylidene)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one(Yoshihama et al. U.S. Pat. No. 6,080,781, Example 11) and2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1)according to Method B (off-white solid, 293 mg). The title compound waslargely present as(±)-2-chloro-4-((3RS,3aRS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74 (qd, J=13.02, 4.69 Hz, 1H),1.65-1.82 (m, 1H), 2.62-2.75 (m, 1H), 2.84 (ddd, J=16.89, 12.60, 4.49Hz, 1H), 3.83 (ddd, J=13.38, 10.84, 4.69 Hz, 1H), 5.80 (d, J=10.94 Hz,1H), 6.58 (d, J=2.34 Hz, 1H), 6.72 (dd, J=8.59, 2.34 Hz, 1H), 6.82-7.50(m, 6H), 7.59 (d, J=8.59 Hz, 1H), 7.88 (d, J=8.59 Hz, 1H), 9.94 (s, 1H).ES-MS m/z 418 (M+H).

Example 87

2-chloro-4-((3R,3aR)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile

The title compound is prepared from the2-chloro-4-(−3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrileprepared in Example 86 using chiral resolution (e.g., Method G).

Example 88

2-chloro-4-((3S,3aS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile

The title compound is prepared from the2-chloro-4-(−3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrileprepared in Example 86 using chiral resolution (e.g., Method G).

Examples 89 and 90, Respectively

3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile

The title compound was prepared from2-(4-fluorobenzylidene)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one(Yoshihama et al. U.S. Pat. No. 6,080,781, Example 11) and4-hydrazinylbenzonitrile hydrochloride (Aldrich) according to Method B.After stirring overnight at 80° C., the reaction mixture wasconcentrated and purified by reverse-phase HPLC (40 to 95%acetonitrile/water/0.05% trifluoroacetic acid). The title compound waslargely present as a mixture of cis and trans diasteromers.

The cis diastereomer,(±)-4-((3RS,3aRS)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile,was the first eluting product (peach colored solid, 187 mg). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.75 (m, 1H), 1.74 (m, 1H), 2.69 (m, 1H), 2.83 (m,1H), 3.80 (ddd, J=13.38, 10.84, 4.69 Hz, 1H), 5.75 (d, J=10.94 Hz, 1H),6.57 (d, J=2.34 Hz, 1H), 6.72 (dd, J=8.59, 2.34 Hz, 1H), 7.12 (m, 5H),7.31 (m, 1H), 7.51 (d, J=8.98 Hz, 2H), 7.85 (d, J=8.59 Hz, 1H), 9.88 (s,1H). ES-MS m/z 384 (M+H). The trans diastereomer,(±)-4-((3RS,3aSR)-3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile,was the second eluting product (peach colored solid, 21.5 mg). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.91 (qd, J=12.76, 5.47 Hz, 1H), 2.17 (m, 1H),2.82 (m, 2H), 3.24 (ddd, J=12.99, 11.03, 4.88 Hz, 1H), 4.90 (d, J=11.33Hz, 1H), 6.61 (d, J=2.34 Hz, 1H), 6.71 (dd, J=8.59, 2.34 Hz, 1H), 6.95(d, J=8.98 Hz, 2H), 7.24 (t, J=8/9 Hz, 2H), 7.47 (m, 2H), 7.53 (d,J=8.98 Hz, 2H), 7.76 (d, J=8.59 Hz, 1H), 9.86 (s, 1H). ES-MS m/z 384(M+H).

Example 91

N-(−2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide

The title compound was prepared fromN-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide;Preparation 36 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride(Preparation 1) according to Method B (tan solid, 159 mg, 0.37 mmol, 59%yield). The title compound was largely present as(±)—N-03RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.59 (m, 7H), 1.65-1.87 (m, 2H),1.98-2.05 (m, 1H), 2.06 (s, 3H), 2.13-2.24 (m, 1H), 2.78-2.97 (m, 2H),3.51 (ddd, J=13.56, 9.26, 4.83 Hz, 1H), 4.86 (dd, J=9.26, 5.50 Hz, 1H),7.11 (dd, J=9.26, 1.48 Hz, 1H), 7.32 (d, J=1.88 Hz, 1H), 7.46 (dd,J=8.59, 1.88 Hz, 1H), 7.60 (s, 1H), 7.64 (d, J=8.86 Hz, 1H), 7.93 (d,J=8.59 Hz, 1H), 10.11 (s, 1H). ES-MS m/z 433 (M+H).

Example 92

2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazol-7-yltrifluoromethanesulfonate

A mixture of3-(4-fluorobenzylidene)-4-oxochroman-7-yltrifluoromethanesulfonate;Preparation 35 (200 mg, 0.50 mmol), 2-chloro-4-hydrazinylbenzonitrilehydrochloride (Preparation 1) (152 mg, 0.75 mmol), and ethanol (5 mL)was stirred under argon at 80° C. for three hours. The mixture wascooled to room temperature and concentrated. Water was added, theresidue extracted three times with methylene chloride, washed withbrine, dried over magnesium sulfate, filtered and condensed. The crudeproduct was purified by normal phase flash column chromatography on a 20g silica gel column (100% methylene chloride). Pure fractions werepooled and condensed to give the title compound (yellow solid, 75 mg,0.14 mmol, 28% yield). The title compound was largely present as(±)-(3SR,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazol-7-yltrifluoromethanesulfonate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.25 (dd,J=12.89, 10.47 Hz, 1H), 4.22-4.35 (m, 1H), 4.42 (dd, J=10.34, 6.04 Hz,1H), 6.00 (d, J=11.28 Hz, 1H), 6.77-7.51 (m, 8H), 7.68 (d, J=8.59 Hz,1H), 8.10 (d, J=9.40 Hz, 1H). ES-MS m/z 553 (M+H).

Example 93

(3S,3aR)-methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

A solution of (trimethylsilyl)diazomethane (2.0 M in diethyl ether,0.286 mL, 0.572 mmol) was added to a solution of(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 16 (200 mg, 0.476 mmol) in tetrahydrofuran (3 mL) andmethanol (1 mL). After 90 minutes, the reaction was concentrated to givethe crude methyl ester (yellow solid, 217 mg). ES-MS m/z 434 (M+H).

Example 94

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3a-methyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid

To a solution of diisopropylamine (0.0772 mL, 0.551 mmol) intetrahydrofuran (1.5 mL) at −78° C. was added n-butyllithium (2.5 M inhexanes, 0.206 mL, 0.514 mmol). After 10 minutes, a solution of(3S,3aR)-methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate,Example 93 (159 mg, 0.367 mmol) in tetrahydrofuran (3.0 mL) was addeddropwise. After 1 hour at −78° C., iodomethane (0.0343 mL, 0.551 mmol)was added. The reaction was kept at −78° C. and monitored by LCMS. After2 hours, another 0.015 mL of iodomethane was added. Lithiumhexamethyldisilazide (1.0 M in tetrahydrofuran, 0.100 mL, 0.100 mmol)was added, followed by another 0.015 mL iodomethane. Allowed to slowlywarm to room temperature overnight. The reaction was treated with 0.5 mLmethanol and 0.5 mL 2.5 N NaOH. After 4 hours, the reaction mixture wasneutralized with 0.5 mL of 3 N hydrogen chloride and concentrated undera stream of nitrogen. The residue was dissolved indimethylformamide/methanol, filtered through a syringe filter andpurified by reverse-phase HPLC (60 to 95% acetonitrile/water/0.05%trifluoroacetic acid) to give the title compound (yellow solid, 48.6 mg,0.112 mmol, 30.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.06 (br. s.,1 H), 8.10 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.69(d, J=9.0 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.57 (d, J=5.9Hz, 1H), 3.01-3.10 (m, 2H), 1.91-2.11 (m, 3H), 1.71-1.82 (m, 1H),1.09-1.56 (m, 7H), 1.06 (s, 3H). ES-MS m/z 434 (M+H).

Example 95

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 3, and 2-(methylsulfonyl)ethanamine hydrochlorideaccording to Method F. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75-0.88 (m,1H), 1.76-1.84 (m, 1H), 2.84-3.02 (m, 2H), 3.03 (s, 3H), 3.38 (t, J=6.85Hz, 2H), 3.67 (q, J=6.62 Hz, 2H), 3.96 (ddd, J=13.43, 11.14, 4.97 Hz,1H), 5.93 (d, J=11.01 Hz, 1H), 6.81-7.44 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.70 (s, 1H), 7.76 (dd, J=8.19, 1.48 Hz, 1H), 8.13 (d, J=8.32 Hz,1H), 8.78 (t, J=5.64 Hz, 1H); HRMS m/z 551.1343 (M+H).

Example 96

2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid and 2-(methylsulfonyl)ethanamine hydrochloride according to MethodF. The title compound was largely present as(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.95-2.07 (m, 1H), 2.22-2.30 (m, 1H),2.92-3.02 (m, 2H), 3.02-3.05 (m, 3H), 3.38 (t, J=6.98 Hz, 2H), 3.41-3.48(m, 1H), 3.65-3.71 (m, 2H), 5.18 (d, J=10.47 Hz, 1H), 6.83 (dd, J=8.86,2.15 Hz, 1H), 7.21 (d, J=2.15 Hz, 1H), 7.25-7.30 (m, 2H), 7.48-7.53 (m,2H), 7.67 (d, J=8.86 Hz, 1H), 7.73 (s, 1H), 7.76 (dd, J=8.19, 1.48 Hz,1H), 8.05 (d, J=8.32 Hz, 1H), 8.79 (t, J=5.64 Hz, 1H); HRMS m/z 551.1310(M+H).

Example 97

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and 2-(methylsulfonyl)ethanamine hydrochloride accordingto Method F. The title compound was largely present as(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.88 (m, 1H), 1.77-1.84 (m, 1H),2.83-2.92 (m, 1H), 2.92-3.00 (m, 1H), 3.03 (s, 3H), 3.37 (t, J=6.85 Hz,2H), 3.63-3.70 (m, 2 H), 3.92-4.01 (m, 1H), 5.93 (d, J=11.01 Hz, 1H),7.07-7.24 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.70 (s, 1H), 7.76 (dd,J=8.19, 1.48 Hz, 1H), 8.14 (d, J=8.32 Hz, 1H), 8.78 (t, J=5.64 Hz, 1H);HRMS m/z 551.1310 (M+H).

Example 98

(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)N-(2-(methylsulfinyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from the trans isomer(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid and amine according to Method F. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.94-2.07 (m, 1H), 2.22-2.30 (m, 1H), 2.58-2.61 (m, 3H), 2.85-2.93 (m,1H), 2.93-3.02 (m, 2H), 3.02-3.10 (m, 1H), 3.39-3.48 (m, 1H), 3.55-3.71(m, 2H), 5.18 (d, J=10.74 Hz, 1H), 6.83 (dd, J=8.86, 2.15 Hz, 1H), 7.21(d, J=2.42 Hz, 1H), 7.24-7.31 (m, 2H), 7.47-7.53 (m, 2H), 7.67 (d,J=8.86 Hz, 1H), 7.74 (s, 1H), 7.76 (dd, J=8.32, 1.34 Hz, 1H), 8.04 (d,J=8.06 Hz, 1H), 8.83 (t, J=5.50 Hz, 1H); HRMS m/z 535.1365 (M+H).

Example 99

(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-N-(2-(methylsulfonyl)ethyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(□)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 36 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.19-1.28 (m, 2H), 1.31-1.42 (m, 1H), 144-1.53 (m, 1H),1.83-1.94 (m, 2H), 2.19-2.29 (m, 1H), 2.56 (s, 3H), 2.82-2.93 (m, 2H),2.95-3.05 (m, 2H), 3.05-315 (m, 2H), 3.53-3.75 (m, 5H), 4.78 (dd,J=9.70, 3.48 Hz, 1H), 7.16 (d, J=8.42 Hz, 1H), 7.40 (s, 1H), 7.66-7.77(m, 3H), 8.03 (d, J=8.05 Hz, 1H), 8.81 (t, J=5.31 Hz, 1H); ES-MS m/z 525(M+H).

Example 100

(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-N-(2-(methylsulfinyl)ethyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 36 and 2-(methylsulfonyl)ethanamine hydrochlorideaccording to Method F. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 125-1.32 (m, 2H),1.41 (ddd, J=24.50, 12.42, 4.43 Hz, 1H), 1.51-1.57 (m, 1H), 1.87-1.99(m, 2H), 2.25-2.33 (m, 1H), 2.87-3.00 (m, 1H), 3.04 (s, 3H), 3.08-3.21(m, 3H), 3.38 (t, J=6.85 Hz, 2H), 3.61-3.79 (m, 5H), 4.82 (dd, J=9.80,3.63 Hz, 1H), 7.18-7.23 (m, 1H), 7.44 (s, 1H), 7.71 (d, J=8.59 Hz, 1 H),7.73-7.77 (m, 1H), 7.78 (s, 1H), 8.08 (d, J=8.06 Hz, 1H), 8.79 (t,J=5.50 Hz, 1H); HRMS m/z 541.1702 (M+H).

Example 101

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-[2-(methylsulfinyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according 25, to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.81 (ddd, J=25.98, 12.69, 4.57 Hz, 1H), 1.70-1.84 (m,3H), 2.27 (t, J=7.38 Hz, 2H), 2.84-3.02 (m, 2H), 3.23-3.30 (m, 2H), 3.96(ddd, J=13.36, 11.35, 4.83 Hz, 1H), 5.92 (d, J=11.01 Hz, 1H), 6.90-7.28(m, 6H), 7.66 (d, J=8.59 Hz, 1H), 7.71 (s, 1H), 7.76 (dd, J=8.32, 1.34Hz, 1H), 8.11 (d, J=8.06 Hz, 1H), 8.53 (t, J=5.50 Hz, 1H), 12.04 (br.s., 1H); HRMS m/z 535.1357 (M+H).

Example 102

(±)-(3RS,3aRS)—N-(3-amino-3-oxopropyl)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.75-0.87 (m, 1H), 1.76-1.84 (m, 1H), 2.34 (t, J=7.12 Hz,2H), 2.83-2.91 (m, 1H), 2.91-3.02 (m, 1H), 3.40-3.46 (m, 2H), 3.64 (br.s., 2H), 3.92-4.00 (m, 1H), 5.93 (d, J=11.01 Hz, 1H), 6.83 (br. s., 1H),7.17 (t, 4H), 7.34 (s, 1H), 7.66 (d, J=8.86 Hz, 1H), 7.70 (s, 1H), 7.75(dd, J=8.06, 1.34 Hz, 1H), 8.11 (d, J=8.06 Hz, 1H), 8.55 (t, J=5.64 Hz,1H); HRMS m/z 516.1587 (M+H).

Example 103

(±)-6-((3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamido)hexanoicacid

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.75-0.87 (m, 1H), 1.76-1.84 (m, 1H), 2.34 (t, J=7.12 Hz,2H), 2.83-2.91 (m, 1H), 2.91-3.02 (m, 1H), 3.40-3.46 (m, 2H), 3.64 (br.s., 2H), 3.92-4.00 (m, 1H), 5.93 (d, J=11.01 Hz, 1H), 6.83 (br. s., 1H),7.17 (t, 4H), 7.34 (s, 1H), 7.66 (d, J=8.86 Hz, 1H), 7.70 (s, 1H), 7.75(dd, J=8.06, 1.34 Hz, 1H), 8.11 (d, J=8.06 Hz, 1H), 8.55 (t, J=5.64 Hz,1H); HRMS m/z 559.1895 (M+H).

Example 104

(±)-5-((3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamido)pentanoicacid

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.81 (ddd, J=25.91, 12.89, 4.97 Hz, 1H), 1.49-1.55 (m,4H), 1.76-1.84 (m, 1H), 2.21-2.26 (m, 2H), 2.84-3.02 (m, 2H), 3.22-3.28(m, 2H), 3.96 (ddd, J=13.56, 11.14, 4.83 Hz, 1H), 5.93 (d, J=11.01 Hz,1H), 7.11-7.24 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.70 (s, 1H), 7.76 (dd,J=8.19, 1.48 Hz, 1H), 8.11 (d, J=8.32 Hz, 1H), 8.51 (t, J=5.64 Hz, 1H),12.02 (br. s., 1H); HRMS m/z 545.1745 (M+H).

Example 105

(±)-(3SR,3aRS)—N-[2-(aminosulfonyl)ethyl]-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 36 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.18-1.28 (m, 2H), 1.31-1.40 (m, 1H), 1.45-1.53 (m, 1H),1.82-1.95 (m, 3H), 2.20-2.30 (m, 1H), 2.83-2.93 (m, 1H), 2.99-3.16 (m,3H), 3.57-3.76 (m, 6H), 4.78 (dd, J=9.52, 3.29 Hz, 1H), 6.92 (s, 2H),7.16 (d, J=8.42 Hz, 1H), 7.40 (s, 1H),

Example 106

(±)-4-((3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamido)butanoicacid

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.75-0.88 (m, 1H), 1.76-1.84 (m, 1H), 2.59 (s, 3 H),2.84-2.92 (m, 2H), 2.92-2.99 (m, 1H), 3.00-3.09 (m, 1H), 3.54-3.70 (m,2H), 3.92-4.01 (m, 1 H), 5.93 (d, J=11.01 Hz, 1H), 6.83-7.47 (m, 6H),7.66 (d, J=8.59 Hz, 1H), 7.71 (s, 1H) 7.77 (dd, J=8.32, 1.61 Hz, 1H),8.13 (d, J=8.06 Hz, 1H), 8.82 (t, J=5.50 Hz, 1H); HRMS m/z 531.1596(M+H).

Example 107

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-N,N-bis(2-(diethylamino)ethyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamidebistrifluoroacetate

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.79 (ddd, J=25.58, 12.69, 4.97 Hz, 1H), 1.03 (br. s.,6H), 1.26 (br. s., 6H), 1.78-1.87 (m, 1H), 2.84-3.06 (m, 6H), 3.14-3.37(m, 8H), 3.58 (br. s., 2H), 3.79 (br. s., 2H), 3.96 (ddd, J=13.29,11.14, 4.83 Hz, 1H), 5.95 (d, J=11.01 Hz, 1H), 7.01-7.29 (m, 6H), 7.36(s, 1H), 7.41 (d, J=8.32 Hz, 1H), 7.67 (d, J=8.86 Hz, 1H), 8.15 (d,J=8.06 Hz, 1H), 9.86 (br. s., 2 H); HRMS m/z 643.3334 (M+H).

Example 108

(±)-2-(2-03RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamido)acetamido)aceticacid

The title compound was prepared from the trans isomer(±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid and amine according to Method F ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.01 (ddd, J=25.11, 12.49, 5.10 Hz, 1H), 2.23-2.31 (m, 1H), 2.92-3.04(m, 2H), 3.45 (ddd, J=13.09, 10.41, 4.97 Hz, 1H), 3.78 (d, J=5.91 Hz, 2H), 3.92 (d, J=5.91 Hz, 2H), 5.18 (d, J=10.47 Hz, 1H), 6.83 (dd, J=8.86,2.15 Hz, 1H), 7.21 (d, J=2.15 Hz, 1H), 7.28 (tt, J=8.86, 1.88 Hz, 2H),7.48-7.53 (m, 2H), 7.67 (d, J=8.86 Hz, 1H), 7.78-7.83 (m, 2 H), 8.05 (d,J=8.06 Hz, 1H), 8.23 (t, J=5.64 Hz, 1H), 8.84 (t, J=5.91 Hz, 1H); HRMSm/z 560.1528 (M+H).

Example 109

(±)-2-(2-((3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamido)ethoxy)aceticacid

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.81 (ddd, J=25.98, 13.09, 4.43 Hz, 1H), 1.77-1.84 (m,1H), 2.84-3.02 (m, 2H), 3.43 (g, J=5.73 Hz, 2H), 3.60 (t, J=5.77 Hz,2H), 3.92-4.00 (m, 1H), 4.04 (s, 2H), 5.93 (d, J=11.28 Hz, 1H),7.04-7.21 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.71 (s, 1H), 7.77 (d,J=8.32 Hz, 1H), 8.12 (d, J=8.06 Hz, 1H), 8.58 (t, J=5.64 Hz, 1H), 12.64(s, 1H); HRMS m/z 547.1522 (M+H).

Example 110

(±)-2-(2-((3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamido)acetamido)aceticacid

The title compound was prepared from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 and amine according to Method F. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.82 (ddd, J=25.98, 12.96, 4.83 Hz, 1H), 1.77-1.85 (m,1H), 2.85-3.04 (m, 2H), 3.77 (d, J=5.91 Hz, 2H), 3.91 (d, J=6.18 Hz,2H), 3.97 (ddd, J=13.49, 11.21, 4.83 Hz, 1H), 5.94 (d, J=11.01 Hz, 1H),6.76-7.43 (m, 6H), 7.67 (d, J=8.86 Hz, 1H), 7.76 (s, 1 H), 7.81 (dd,J=8.32, 1.34 Hz, 1H), 8.14 (d, J=8.32 Hz, 1H), 8.22 (t, J=5.77 Hz, 1H),8.83 (t, J=5.91 Hz, 1H) 12.55 (s, 1H); HRMS m/z 560.1491 (M+H).

Example 111

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(77 mg, 0.24 mmol) was added to a solution of(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 (89 mg, 0.20 mmol), triethylamine (0.056 mL, 0.40 mmol),and dimethylformamide (2.0 mL) at room temp. After 10 minutes,2-(pyrrolidin-1-yl)ethanamine (0.051 mL, 0.40 mmol) was added. After 40minutes, the reaction was quenched with 0.30 mL 3N hydrogen chloride andpurified by reverse-phase HPLC (20 to 90% acetonitrile/water/0.05%trifluoroacetic acid). The purified fractions were combined, neutralizedwith saturated sodium bicarbonate solution, and concentrated until aprecipitate formed. The precipitate was filtered, washed with water, anddried to give the title compound (yellow solid, 45.5 mg, 0.084 mmol, 42%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (m, 1H), 1.64 (m, 4H), 1.79(m, 1H), 2.46 (m, 4H), 2.54 (t, J=7.03 Hz, 2H), 2.91 (m, 2H), 3.35 (q,J=6.64 Hz, 2H), 3.95 (ddd, J=13.57, 11.03, 5.08 Hz, 1H), 5.92 (d,J=11.33 Hz, 1H), 7.15 (m, 6H), 7.65 (d, J=8.59 Hz, 1H), 7.69 (s, 1H),7.75 (dd, J=8.20, 1.56 Hz, 1H), 8.10 (d, J=8.20 Hz, 1H), 8.47 (t, J=5.86Hz, 1H). ES-MS m/z 542 (M+H).

Example 112

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-8-carboxamide

The title compound was prepared according to the procedure described forExample 111 from(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-8-carboxylicacid, Example 5. Off-white solid, 45.7 mg. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.79 (qd, J=12.89, 5.08 Hz, 1H), 1.68 (m, 4H), 1.79 (m, 1H), 2.48(m, 4H), 2.58 (t, J=7.03 Hz, 2H), 2.92 (m, 2H), 3.40 (m, 2H), 3.95 (m,1H), 5.91 (d, J=10.94 Hz, 1H), 7.15 (m, 6H), 7.31 (d, J=7.81 Hz, 1H),7.66 (d, J=8.98 Hz, 1H), 7.79 (dd, J=8.01, 1.76 Hz, 1H), 8.49 (d, J=1.95Hz, 1H), 8.59 (t, J=5.66 Hz, 1H). ES-MS m/z 542 (M+H).

Example 113

(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(methylsulfonyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

A solution of(±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 2 (45 mg, 0.10 mmol), methylsulfonamide (12 mg, 0.12mmol), triethylamine (0.021 mL, 0.15 mmol), and tetrahydrofuran (1.0 mL)was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (29 mg, 0.15 mmol) followed by 4-dimethylaminopyridine (15mg, 0.12 mmol) at room temp. The reaction was stirred at room tempovernight. The reaction was concentrated and purified by reverse-phaseHPLC (40 to 95% acetonitrile/water/0.05% trifluoroacetic acid) to givethe title compound (yellow solid, 20.6 mg, 0.0394 mmol, 39% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.70-0.92 (m, 1H), 1.72-1.89 (m, 1H),2.84-3.04 (m, 2H), 3.35 (s, 3H), 3.98 (ddd, J=13.67, 10.94, 5.08 Hz,1H), 5.95 (d, J=11.33 Hz, 1H), 6.65-7.58 (m, 6H), 7.67 (d, J=8.98 Hz,1H), 7.75-7.89 (m, 2H), 8.16 (d, J=8.20 Hz, 1H), 12.17 (s, 1H). ES-MSm/z 523 (M+H).

Example 114

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

To a solution of(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 (90 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) wasadded 1-hydroxybenzotriazole (43 mg, 0.32 mmol), triethylamine (0.06 mL,0.40 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (103 mg, 0.32 mmol). The solution was stirred forfifteen minutes followed by addition of 2-(methylsulfonyl)ethanamine (40mg, 0.32 mmol). The solution was stirred for twenty hours at ambienttemperature. The reaction was quenched with water and the resultingyellow solid was collected by vacuum filtration. Chromatography (reversephase, acetonitrile/water) provided(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide(yellow solid, 55 mg, 52% yield). LC/MS on 4.6×50 mm C-18 column,t_(R)=6.01 minutes (10 to 90% acetonitrile/water over 6 minutes at 2mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 525 (M+H)

Example 115

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-hydroxyethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

To a solution of(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 (90 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) wasadded 1-hydroxybenzotriazole (43 mg, 0.32 mmol), triethylamine (0.06 mL,0.40 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (103 mg, 0.32 mmol). The solution was stirred fortwenty-five minutes followed by addition of ethanolamine (0.02 mL, 0.32mmol). The solution was stirred for twenty hours at ambient temperature.The reaction was quenched with water and the resulting yellow solid wascollected by vacuum filtration. Chromatography (reverse phase,acetonitrile/water) provided(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-hydroxyethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide(yellow solid, 30 mg, 33% yield). LC/MS on 4.6×50 mm C-18 column,t_(R)=6.00 minutes (10 to 90% acetonitrile/water over 6 minutes at 2mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 463 (M+H); HRMSCalculated for C₂₆H₂₇ClN₄O₂: 463.1895 (M+H)⁺. Found: 463.1875; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 110-1.50 (m, 6H), 1.66-1.84 (m, 2H), 2.17-2.25(m, 1H), 2.87-2.93 (m, 1H), 2.99-3.06 (m, 1H), 3.26-3.34 (m, 2H), 3.48(t, J=6.18 Hz, 2 H), 3.53-3.63 (m, 2H), 4.92 (dd, J=9.13, 6.18 Hz, 1H),7.17 (dd, J=8.46, 1.75 Hz, 1H), 7.38 (d, J=2.15 Hz, 1H), 7.65 (d, J=8.86Hz, 1H), 7.73 (d, J=8.59 Hz, 1H), 7.76 (s, 1H), 8.03 (d, J=8.06 Hz, 1H),8.46 (t, J=6.31 Hz, 1H).

Example 116

(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-sulfamoylethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

To a solution of(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 (100 mg, 0.24 mmol) in N,N-dimethylformamide (3 mL) wasadded 1-hydroxybenzotriazole (48 mg, 0.36 mmol), triethylamine (0.07 mL,0.48 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (115 mg, 0.36 mmol). The solution was stirred forfifteen minutes followed by addition of 2-aminoethanesulfonamide (44 mg,0.36 mmol). The solution was stirred for twenty hours at ambienttemperature. The reaction was partitioned between ethyl acetate andwater. The organic layer was washed with water and brine and dried overmagnesium sulfate. Chromatography (reverse phase, acetonitrile/water)provided(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-sulfamoylethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide(yellow solid, 10 mg, 8% yield). LC/MS on 4.6×50 mm C-18 column,t_(R)=5.80 minutes (10 to 90% acetonitrile/water over 6 minutes at 2mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 526 (M+H).

Example 117

(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from(3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 40, and 2-(methylsulfonyl)ethanamine hydrochlorideaccording to Method F (35 mg, 70% yield). ¹H NMR (400 MHz, DMSO-d₆)water suppression, δ ppm 1.19-1.21 (m, 1H), 1.91 (d, J=9.88 Hz, 1H),2.07 (s, 3H), 2.96 (d, J=16.84 Hz, 2H), 3.01 (s, 3H), 3.63-3.66 (m, 2H),3.86 (br. s., 1H), 5.92 (d, J=16.47 Hz, 1H), 5.95 (br. s., 1H), 6.27 (d,J=2.93 Hz, 1H), 7.06 (br. s., 1H), 7.33 (br. s., 1H), 7.65-7.74 (m, 3H),8.08 (d, J=8.05 Hz, 1H), 8.77 (t, J=5.49 Hz, 1H); ES-MS m/z 537 (M+H).

Example 118

2-(3-chloro-4-cyanophenyl)-N-[2-(methylsulfonyl)ethyl]-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide

The title compound was prepared from2-(3-chloro-4-cyanophenyl)-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 49 (40 mg, 0.09 mmol) and 2-(methylsulfonyl)ethanaminehydrochloride (15 mg, 0.09 mmol) according to Method F in 72% yield. Thetitle compound was largely present as3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-N-[2-(methylsulfonyl)ethyl]-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (dd, J=12.70, 5.27 Hz, 1H), 1.95(dd, J=8.79, 3.32 Hz, 1H), 2.50 (s, 3H), 2.96-3.05 (m, 2H), 3.04 (s,3H), 3.38 (s, 3H), 3.68 (q, J=6.64 Hz, 2H), 3.94 (br. s., 1H), 6.31 (d,J=10.16 Hz, 1H), 7.10 (br.s., 1H), 7.40 (br. s., 1H), 7.64 (s, 1H), 7.72(d, J=8.98 Hz, 1H), 7.77-7.87 (m, 2H), 8.14 (d, J=8.20 Hz, 1H), 8.80 (t,J=5.66 Hz, 1H); ES-MS m/z 554 (M+H).

Example 119

(±)-(3SR,3aRS)-isopropyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and propan-2-ol according to Method E (yellow solid,145 mg, 0.313 mmol, 66% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (d,J=8.1 Hz, 1H), 7.89-7.94 (m, 2H), 7.46 (d, J=8.9 Hz, 1H), 7.30 (d, J=2.1Hz, 1H), 7.03 (dd, J=8.9, 2.1 Hz, 1H), 5.22-5.32 (m, 1H), 4.63 (dd,J=9.7, 5.4 Hz, 1H), 3.44-3.54 (m, 1H), 3.08-3.16 (m, 1H), 2.86-2.98 (m,1, 2.25-2.36 (m, 1H), 2.07-2.19 (m, 1H), 1.88-2.03 (m, 1H), 1.73-1.83(m, 1H), 1.42-1.66 (m, 5H), 1.39 (d, J=6.4 Hz, 6H), 1.20-1.37 (m, 2H).ES-HRMS m/z calc. for C₂₇H₂₉ClN₃O₂ (M+H) 462.1943. found 462.1897.

Example 120

(±)-(3SR,3aRS)-2-cyclohexylethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and 2-cyclohexylethanol according to Method E (yellowsolid, 172 mg, 0.325 mmol, 68% yield). ES-HRMS m/z calc. forC₃₂H₃₇ClN₃O₂ (M+H) 530.2569. found 530.2534.

Example 121

(±)-(3SR,3aRS)-cyclohexylmethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and cyclohexylmethanol according to Method E (yellowsolid, 165 mg, 0.320 mmol, 67% yield). ES-HRMS m/z calc. forC₃₁H₃₅ClN₃O₂ (M+H) 516.2412. found 516.2403.

Example 122

(±)-(3SR,3aRS)-((R)-sec-butyl)2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and (R)-butan-2-ol according to Method E (yellow solid,155 mg, 0.326 mmol, 68% yield). ES-HRMS m/z calc. for C₂₈H₃₁ClN₃O₂ (M+H)476.2099. found 476.2100.

Example 123

(±)-(3SR,3aRS)-2-(2-(2-ethoxyethoxy)ethoxy)ethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and 2-(2-(2-methoxyethoxy)ethoxy)ethanol according toMethod E (yellow solid, 199 mg, 0.352 mmol, 74% yield). ES-HRMS m/zcalc. for C₃₁H₃₆ClN₃NaO₅ (M+Na) 588.2241. found 588.2245.

Example 124

(±)-(3SR,3aRS)-2-(2-(2-hydroxyethoxy)ethoxy)ethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and triethylene glycol according to Method E (yellowsolid, 125 mg, 0.226 mmol, 47% yield). ES-HRMS m/z calc. forC₃₀H₃₄ClN₃NaO₅ (M+Na) 574.2085. found 574.2047.

Example 125

(±)-(3SR,3aRS)-2-(bis(2-hydroxyethyl)amino)ethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and triethanolamine according to Method E. ¹H NMR (400MHz, CDCl₃) δ ppm 1.17-1.66 (m, 7H), 1.70-1.82 (m, 1H), 1.88-2.02 (m, 1H), 2.06-2.18 (m, 1H), 2.23-2.45 (m, 1H), 2.79-2.85 (m, 4H), 2.86-2.97(m, 1H), 3.03 (t, J=5.50 Hz, 2H), 3.07-3.17 (m, 1H), 3.48 (ddd, J=13.90,9.47, 4.83 Hz, 1H), 3.63-3.70 (m, 4H), 4.48 (t, J=5.50 Hz, 2H), 4.63(dd. J=9.40, 5.37 Hz, 1H), 7.01 (dd, J=8,86, 2.15 Hz, 1H), 7.29 (d,J=2.15 Hz, 1H), 7.45

Example 126

(±)-(3SR,3aRS)-pentan-3-yl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and pentan-3-ol according to Method E. ¹H NMR (400 MHz,CDCl₃) δ ppm 0.97 (t, J=7.38 Hz, 6H), 1.18-1.63 (m, 7H), 1.64-1.81 (m,4H), 1.96 (ddd, J=26.11, 12.96, 4.16 Hz, 1H), 2.06-2.18 (m, 1H),2.23-2.40 (m, 1H), 2.83-3.01 (m, 1 H), 3.07-3.18 (m, 1H), 3.49 (ddd,J=13.76, 9.33, 4.83 Hz, 1H), 4.64 (dd, J=9.67, 5.37 Hz, 1H), 5.04 (dt,J=12.35, 6.18 Hz, 1H), 7.03 (dd, J=8.86, 2.15 Hz, 1H), 7.30 (d, J=2.15Hz, 1H), 7.46 (d, J=8.86 Hz, 2

Example 127

(±)-(3SR,3aRS)-cyclohexyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and cyclohexanol according to Method E. ¹H NMR (400MHz, CDCl₃) δ ppm 1.19-1.68 (m, 13H), 1.70-1.86 (m, 3H), 1.87-2.03 (m, 3H), 2.06-2.20 (m, 1H), 2.23-2.39 (m, 1H), 2.85-2.98 (m, 1H), 3.13 (ddd,J=16.18, 3.36, 3.02 Hz, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H),4.63 (dd, J=9.53, 5.50 Hz, 1H), 5.04 (ddd, J=12.82, 8.93, 3.76 Hz, 1H),7.02 (dd, J=8.86, 1.88 Hz, 1H), 7.30 (d, J=2.15 Hz, 1H), 7.46 (d, J=8.86Hz, 1H), 7.87-7.97 (m, 2H), 8.14 (d, J=8.32 Hz, 1H).

Example 128

(±)-(3SR,3aRS)-2-methoxy-2-oxoethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and methyl glycolate according to Method E. ¹H NMR (400MHz, CDCl₃) δ ppm 1.20-1.69 (m, 7H), 1.72-1.84 (m, 1H), 1.89-2.03 (m, 1H), 2.06-2.20 (m, 1H), 2.26-2.36 (m, 1H), 2.86-2.99 (m, 1H), 3.07-3.18(m, 1H), 3.49 (ddd, J=13.70, 9.40, 4.83 Hz, 1H), 3.82 (s, 3H), 4.65 (dd,J=9.53, 5.50 Hz, 1H), 4.89 (s, 2H) 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.31(d, J=1.88 Hz, 1H), 7.46 (d, J=8.86 Hz, 1H), 7.95-8.01 (m, 2H), 8.17 (d,J=8.86 Hz, 1H). ES-MS m/z 492 (M+H).

Example 129

(±)-(3SR,3aRS)-2-ethoxy-2-oxoethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and ethyl glycolate according to Method E. ¹H NMR (400MHz, CDCl₃) δ ppm 1.32 (t, J=7.12 Hz, 4H), 1.40-1.67 (m, 6H) 1.72-1.83(m, 1H), 1.96 (ddd, J=26.25, 13.09, 4.16 Hz, 1H), 2.06-2.20 (m, 1H),2.25-2.36 (m, 1H), 2.84-2.99 (m, 1 H), 3.12 (ddd, J=16.18, 3.36, 3.02Hz, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H), 4.28 (q, J=7.25 Hz, 2H), 4.64 (dd, J=9.67, 5.37 Hz, 1H), 4.87 (s, 2H), 7.03 (dd, J=8.73, 2.01Hz, 1H), 7.31 (d, J=2.15 Hz, 1 H), 7.46 (d, J=8.59 Hz, 1H), 7.93-8.02(m, 2H), 8.17 (d, J=8.86 Hz, 1H). ES-MS m/z 506 (M+H).

Example 130

(±)-(3SR,3aRS)-2-(benzyloxy)-2-oxoethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and benzyl glycolate according to Method E. ¹H NMR (400MHz, CDCl₃) δ ppm 1.20-1.68 (m, 7H), 1.72-1.84 (m, 1H), 1.96 (ddd,J=26.18, 12.89, 4.16 Hz, 1H), 2.06-2.20 (m, 1H), 2.25-2.35 (m, 1H),2.84-2.98 (m, 1H), 3.12 (ddd, J=15.91, 3.36, 3.02 Hz, 1H), 3.49 (ddd,J=13.83, 9.40, 4.70 Hz, 1H), 4.65 (dd, J=9.40, 5.37 Hz, 1H), 4.92 (s,2H), 5.25 (s, 2H), 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.31 (d, J=2.15 Hz,1H), 7.33-7.42 (m, 5H), 7.46 (d, J=8.86 Hz, 1H), 7.93-8.03 (m, 2H), 8.17(d, J=8.59 Hz, 1H).

Example 131

(±)-(3SR,3aRS)-(9H-fluoren-9-yl)methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and 9-fluorenylmethanol according to Method E. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.19-1.67 (m, 7H), 1.72-1.85 (m, 1H), 1.99 (ddd,J=26.11, 12.96, 4.16 Hz, 1H), 2.07-2.22 (m, 1H), 2.25-2.38 (m, 1H),2.85-3.03 (m, 1H), 3.06-3.21 (m, 1H), 3.50 (ddd, J=13.83, 9.26, 4.83 Hz,1H), 4.41 (t, J=7.12 Hz, 1H), 4.60-4.70 (m, 3H), 7.03 (dd, J=8.73, 2.01Hz, 1H), 7.29-7.38 (m, 3H), 7.40-7.51 (m, 3H), 7.66 (d, J=7.52 Hz, 2H),7.82 (d, J=7.52 Hz, 2H), 7.91-8.00 (m, 2H), 8.20 (d, J=8.06 Hz, 1H).

Example 132

(±)-(3SR,3aRS)-2-(pyridin-2-yl)ethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared according to Method E from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and 2-(2-pyridyl)ethanol. Yellow solid, 194 mg. ES-MSm/z 525 (M+H).

Example 133

(±)-(3SR,3aRS)-4-methoxybenzyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared according to Method E from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and p-methoxybenzyl alcohol. Yellow solid, 194 mg.ES-MS m/z 540 (M+H).

Example 134

(±)-(3SR,3aRS)-benzyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared according to Method E from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and benzyl alcohol. Yellow solid, 193 mg. ES-MS m/z 510(M+H).

Example 135

(±)-(3SR,3aRS)-2-(triethylsilyl)ethyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared according to Method E from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and 2-(trimethylsilyl)ethanol. Yellow solid, 192 mg.ES-MS m/z 520 (M+H).

Example 136

(±)-(3SR,3aRS)-heptyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and 1-heptanol according to Method E. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.86 (t, J=6.98 Hz, 3H), 1.11-1.56 (m, 15H), 1.67-1.75(m, 3H), 1.83 (ddd, J=25.98, 12.82, 3.89 Hz, 1H), 2.01-2.12 (m, 1H),2.20-2.27 (m, 1H), 2.85-2.96 (m, 1H), 3.07-3.15 (m, 1H), 3.62 (ddd,J=13.76, 9.33, 4.56 Hz, 1H), 4.28 (t, J=6.58 Hz, 2H), 4.97 (dd, J=9.40,5.64 Hz, 1H), 7.21 (dd, J=8.86, 2.15 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H),7.69 (d, J=8.86 Hz, 1 H), 7.83 (dd, J=8.19, 1.48 Hz, 1H), 7.87 (s, 1H),8.12 (d, J=8.32 Hz, 1H); ES-MS m/z 518 (M+H).

Example 137

(±)-(3SR,3aRS)-butyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate

The title compound was prepared from(±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid, Example 15 and n-butanol according to Method E. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.94 (t, J=7.38 Hz, 3H), 1.12-1.55 (m, 9H), 1.66-1.75 (m,3H), 1.83 (ddd, J=25.91, 13.02, 4.03 Hz, 1H), 2.01-2.11 (m, 1H),2.20-2.27 (m, 1H), 2.85-2.96 (m, 1H), 3.07-3.15 (m, 1H), 3.61 (ddd,J=13.63, 9.33, 4.70 Hz, 1H), 4.29 (t, J=6.44 Hz, 2H), 4.97 (dd, J=9.53,5.77 Hz, 1H), 7.21 (dd, J=8.86, 1.88 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H),7.69 (d, J=8.86 Hz, 1H), 7.83 (dd, J=8.32, 1.34 Hz, 1H), 7.87 (s, 1H),8.12 (d, J=8.32 Hz, 1H); ES-MS m/z 476 (M+H).

O. BIOLOGICAL ASSAYS 1. In Vitro Assay Method 1: Cell-based Gal4Response Element-controlled Luciferase Reporter Assay

An in vitro assay can be used to evaluate mineralocorticoid receptor(MR) antagonism by a test compound. As described more specificallybelow, this assay measures the mineralocorticoid receptor IC₅₀ value ofthe test compound (i.e., the concentration of the test compound requiredto block agonist induced activation of the mineralocorticoid receptor by50%, relative to activation in the absence of an antagonist. Human livercells (Huh7) were transfected with a luciferase reporter gene under thecontrol of Gal4 response element, along with a plasmid containing theGal4 DNA binding domain (DBD) fusion of a steroid receptor(mineralocorticoid receptor) ligand binding domains (LBDs) and a3-galactosidase control plasmid. An agonist of the receptor can bind toand activate the receptor LBD, which activate the expression of the Gal4response element containing luciferase reporter gene. Antagonists cancompete for binding to the receptor LBDs and decrease the transcriptionactivity of the reporter gene. Measurement of luciferase activity allowsquantitative determinations of the reporter transcription in thepresence of either agonists or agonists and antagonists in combination.β-galactosidase activity, which is unaffected by ligand, is used tonormalize the transfection efficiency in the cell population.

Huh7 cells were plated in RPMI 1640+10% fetal bovine serum (InvitrogenCorporation, San Diego, Calif.), at 10,000 cells per well in 96-welltissue culture dishes for approximately 24 hours. Cells were thentransfected using FuGENE™ 6 Transfection Reagent according tomanufacturers' instructions (Roche Molecular Biochemicals, Indianapolis,Ind.). Approximately 20 hours after transfection, media were removed.Cells were washed once with PBS and treated (n=6/group) with agonist foreach receptor (all chemicals from Sigma, St. Louis, Mo.), and withcompounds. Agonist concentrations represent 70-80% of full activation ofeach receptor.

Compounds were dissolved in DMSO at 10 mM and diluted to finalconcentrations in phenol red-free media that contained 10% charcoal- anddextran-stripped serum (Life Technologies, Gathersburg, Md.). Followingovernight incubation (18-20 hours) with compounds, the medium wasremoved and replaced with 100 μL per well of PBS and 100 μL ofSteady-Glo™ lysis buffer with luciferase substrate (Promega Corporation,Madison, Wis.). After a 30-minute incubation to completely lyse thecells, 100 μL of the lysate was transferred to a black, DynatechMicrofluor assay plates (Dynex Corporation, Chantilly, Va.) to measureluciferase activity. The plate was sealed with TopSeal self-adhesivefilm, dark-adapted for 5 minutes, then counted in a TopCount PlateReader (Packard Instrument Company, Meriden, Conn.) in single photoncounting mode. The remaining lysate was used for determination ofβ-galactosidase activity. In a clear 96-well assay plate, 100 μL of celllysate was added to 100 μL β-galactosidase assay buffer per well. Theassay buffer consisted of 60 mM Na₂HPO₄, 40 mM NaH2PO₄, 10 mM KCl, 1 mMMgSO₄, 50 mM β-mercaptoethanol, and 2.5 mg/mL ONPG, the latter tworeagents were added just prior to assay (all chemicals from Sigma). Thereaction was allowed to proceed until a distinct yellow color developed.Reactions were stopped by the addition of 100 μL per well 1 M Na₂CO₃ andplates were read at 420 nm in Victor-2 (Perkin Elmer Life Sciences,Boston, Mass.). Values (relative luciferase activity) for each samplewere expressed as a ratio of luciferase activity to OD₄₂₀β-galactosidase activity measured in arbitrary units for each well.Curve fitting was performed using the 4-parameter logistic model(y=(a−d)/(1+(x/c)̂13)+d) with the lower (a) and upper (d) plateausrepresenting activity values for vehicle control and agonist controlrespectively. “b” is the slope, “c” is the IC₅₀ or EC₅₀. “x” is theconcentration of the compound and “y” the activity at thatconcentration.

Compounds were tested in accordance with the above described assayyielding the IC₅₀ values described below:

Example # MR IC₅₀ (uM) 1 1.07 2 0.223 3 0.0407 4 3.5 5 3.7 6 0.081 70.0172 8 2.74 9 0.17 10 0.553 11 0.205 12 >10.0 13 0.535 14 0.929 150.0212 16 0.0085 17 0.958 18 0.089 19 0.0376 20 2.88 21 0.004 22 0.00423 >0.500 24 0.008 25 0.007 26 0.013 27 0.305 28 0.15 29 >1.00 30 0.44631 0.488 33 >0.500 34 0.72 35 0.021 36 0.127 37 >1.00 38 >1.00 39 0.02240 0.006 41 >1.00 42 0.015 43 0.021 44 0.016 45 >1.00 46 0.069 47 0.01848 >1.00 49 0.103 50 0.205 51 0.007 52 4.98 53 0.307 54 0.973 55 0.84956 0.302 57 3.51 58 3.18 59 >1.00 60 >1.00 61 0.039 62 0.026 63 >1.00 640.065 65 0.038 66 3.35 67 0.146 68 0.052 69 0.13 70 0.906 71 0.205 728.1 73 0.167 74 0.588 75 0.711 76 >1.00 77 0.013 78 0.07 79 6.92 800.049 81 0.035 82 >1.00 83 0.077 84 0.113 85 >1.00 86 0.086 87 0.03688 >1.00 89 0.705 90 1.1 91 0.005 92 >1.00 94 0.025 95 0.002 96 0.012 970.012 98 0.013 99 0.014 100 0.021 101 0.023 102 0.035 103 0.113 1040.122 105 0.141 106 0.312 107 0.523 108 >1.00 109 >1.00 110 >1.00 1110.057 112 1.55 113 0.995 114 0.001 115 0.003 117 0.003 118 0.0192. In Vivo assays

Method 2: Colonic ENaCgamma Expression Assay

The effect of a test compound can also be evaluated for potentialtherapeutic applications by a functional assay, in which the testcompound blocks in vivo expression of a surrogate protein marker formineralocorticoid receptor activation. In this assay aldosterone inducedexpression of colonic ENaCgamma is measured. Male Sprague-Dawley rats(225-250 g) (Harlan Sprague-Dawley Industries, Indianapolis, Ind.) wereused in this assay. All animals were housed in a room with ambienttemperature of 22±1° C. on a 12 hour light/dark cycle. Animals wereallowed one week to acclimate and had free access to Teklad 22/5 rodentchow (Harlan Teklad, Madison, Wis.) and tap water ad libitum until theinitiation of the study.

The rats were initially anesthetized with 5% Isoflurane (AErrane;Baxter, Inc., Deerfield, Ill.) delivered in 100% O₂ (USP Medical Grade,Airgas-Mid America, Bowling Green, Ky.) using a VMS anesthesiainstrument (Matrix Medical, Inc., Orchard Park, N.Y.) Once anesthetized,1-2% Isoflurane was used to maintain anesthesia. The surgery site wasshaved, scrubbed with Dial 4% CHG surgical scrub (Dial Corp., Phoenix,Ariz.), and sprayed with Betadine Aerosol topical antiseptic/bactericidespray (Perdue Frederick Co., Stamford, Conn.), and a bilateraladrenalectomy (ADX) was performed via the dorsal approach. The musclelayer was closed with 4-0 vicryl and skin wounds closed with surgicalstaples. The analgesic, Marcaine (0.25%) (Abbot Laboratories, Chicago,Ill.) was injected (0.1 mL, s.c.) at the incision site. Post-operativecare included monitoring of the animals, which were placed onthermogenic heating pads during recovery from anesthesia until sternalrecumbency and alertness were obtained. Animals were inspected daily forsigns of distress and infection at the surgical site. ADX rats weregiven 0.9% NaCl in the drinking water to compensate the sodiumdeficiency induced by the ADX.

After 3 days of recovery from surgery, and following an overnight fast,rats were randomly assigned into five groups (n=5-9), including threetreatment groups, one control group and one vehicle group. The vehicleand control groups were dosed with solution vehicle (10% EtOH, 70% PEG400, 20% PBS); the rats in the treatment groups were dosed orally withtest compounds at 1 mg/kg, dissolved in the solution vehicle.Aldosterone (5 ug/kg, Sigma, St. Louis, Mo.) was given to all treatmentgroups and the control group at 30 minutes post-dose. Blood and distalcolon were collected at 2 hours post-dose. The rats were sacrificed withCO₂ and animals were exsanguinated using an 18-gauge needle insertedinto the heart. The distal colon was extracted and immediately placed inliquid N2 for later ENaCγ level determination. Blood was centrifuged for15 minutes at 3000 rpm, 4° C. and serum collected and frozen at −80° C.until further analysis.

Frozen distal colon was powdered, lysed in Qiagen RLT buffer withchloroform, and the aqueous layer combined with 70% ethanol and purifiedover the Qiagen 96-well RNeasy system (Qiagen Inc, Valencia, Calif.). 5ul reactions were prepared with the Bioimaek 2000 and Fx instruments,and Q-RT-PCR was performed using Qiagen one-step reagents. Thermocyclingand data collection were performed on an ABI 7900 (Applied Biosystems,Foster City, Calif.). The comparative CT (threshold cycle) method ofcalculation was used for determining relative expression ofmineralocorticoid receptor target genes; cyclophilin was used tonormalize expression.

Method 3: Dahl SS Rat Blood Pressure Assay

The effect of a test compound on systemic blood pressure can beevaluated in vivo, using an animal model of hypertension. Male Dahlsalt-sensitive rats (225-250 g) (Harlan Sprague-Dawley Industries,Indianapolis, Ind.) were used in this assay. All animals were housed ina room with ambient temperature of 22±1° C. on a 12 hour light/darkcycle. Animals were allowed one week to acclimate and had free access toTeklad 22/5 rodent chow (Harlan Teklad, Madison, Wis.) and tap water adlibitum until the initiation of the study.

All animals were instrumented with radiotelemetry units (Data SciencesInc., St. Paul, Minn.) for conscious, unrestricted SBP measurements.Animals were initially anesthetized with 5% Isoflurane (AErrane; Baxter,Inc., Deerfield, Ill.) delivered in 100% O₂ (USP Medical Grade,Airgas-Mid America, Bowling Green, Ky.) using a VMS anesthesiainstrument (Matrix Medical, Inc., Orchard Park, N.Y.). Onceanesthetized, 1-2% Isoflurane was used to maintain anesthesia. Thesurgery site was shaved, scrubbed with Dial 4% CHG surgical scrub (DialCorp., Phoenix, Ariz.), and sprayed with Betadine Aerosol topicalantiseptic/bactericide spray (Perdue Frederick Co., Stamford, Conn.). A5-cm midline incision was made through the skin and muscle layer of theabdominal wall exposing the peritoneal cavity. Organs were carefullydisplaced with tissue retractors in order to expose the abdominal aortaand mesentery. A 1.5-cm segment between the renal arteries and thebifurcation of the iliac arteries was exposed and an anchor was madeusing 4-0 silk suture adjacent to the aorta in the psoas muscle.Microvessel clips were placed at both ends of the cleared aorta to stopexcessive blood flow, and the aorta was cannulated using a 21-gauge bentneedle to insert the indwelling radiotelemetry probe-flow catheter. Thecatheter was secured to the psoas muscle using the 4-0 silk anchor,microvessel clips and retractor were removed, and organs repositioned.The body of the telemetry unit was placed on top of the lower intestinesand 1 mL of warm saline dripped into the body cavity. Using aninterrupted suture pattern with 4-0 vicryl, the transmitter was sewninto the muscle layer, the abdominal wall was closed, and the skin layerwas closed using 4-0 ethilon (nylon) suture in an interrupted pattern.The analgesic, Marcaine (0.25%) (Abbot Laboratories, Chicago, Ill.) wasinjected (0.1 mL, s.c.) at the incision site. Post-operative careincluded treatment with 0.1 mg/kg, s.c. Buphrenorphine (Rickett & ColmanPharmaceuticals Inc., Richmond, Va.) and monitoring of the animals,which were placed on thermogenic heating pads during recovery fromanesthesia until sternal recumbency and alertness were obtained. Animalswere inspected daily for signs of distress and infection at the surgicalsite.

After 5-7 days of recovery from surgery, baseline SBP was measured andall animals were then randomized to various treatment groups andcompounds were continued for 21 days. All animals were placed on Teklad92034 4% NaCl rodent chow (Harlan Teklad), which was maintained for 21days. The vehicle group received 0.5% methylcellulose/0.1% Tween 80. Allcompounds given to the treatment groups were dissolved in 0.5%methylcellulose/0.1% Tween 80. For compound treated groups, animals weredosed with the compounds daily, via gavage. For eplerenone treatedgroups, eplerenone was incorporated into the 4% NaCl rodent chow atvarious concentrations (Research Diets, Inc., New Brunswick, N.J.).

Radiotelemetrized arterial SBP was measured with the DATAQUEST A.R.T.Version 3.0—Gold software (Data Sciences International, St. Paul,Minn.). The values represent the average of all data points collectedfrom each animal, every 15 minutes for a 10 second interval over a24-hour period (6:00 a.m. to 6:00 a.m. the following day). SBP data wascollected continuously over the course of the entire study (days 1-21).

Twenty-four hours prior to the termination of the study, animals wereplaced in metabolism caging and urine was collected at 24 hours. Animalswere not fasted for the 24-hour period. After 21 days of treatment,animals were anesthetized with a mixture of ketamine (40 mg/kg) andxylazine (5 mg/kg) (i.p.) and weighed with a Mettler PM6000 balance(Mettler-Toledo, Inc., Hightstown, N.J.). Animals were exsanguinatedusing a 20-gauge needle inserted into the abdominal aorta. Blood sampleswere immediately transferred into Vacutainer collection tubes(Becton-Dickinson and Co., Franklin Lakes, N.J.) and placed on wet ice.Blood was centrifuged for 15 minutes at 3000 rpm, 4° C. and plasmacollected and frozen at −80° C. until further analysis. Plasma and urinechemistries (e.g., albumin, creatinine and electrolytes) were analyzedwith the Hitachi 912 automated diagnostic clinical chemistry analyzer(Roche Diagnostics Corp., Indianapolis, Ind.) according to standardprocedures.

All mentioned documents are incorporated by reference as if hereinwritten. When introducing elements of the present invention or theexemplary embodiment(s) thereof, the articles “a,” “an,” “the” and“said” are intended to mean that there are one or more of the elements.The terms “comprising,” “including” and “having” are intended to beinclusive and mean that there may be additional elements other than thelisted elements. Although this invention has been described with respectto specific embodiments, the details of these embodiments are not to beconstrued as limitations.

1. A compound, or a pharmaceutically acceptable salt of the compound,wherein the compound has the structure of Formula I:

wherein: X is selected from the group consisting of —CH₂— and —O—; R¹ isselected from the group consisting of cyclopentyl and phenyl; whereinthe R¹ cyclopentyl and phenyl substituents may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of chloro, fluoro, methyl, ethyl, propyl, chloromethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl andtrifluoromethyl; R² is selected from the group consisting of hydrogenand alkyl; R^(3A) and R^(3B) are independently selected from the groupconsisting of hydrogen and alkyl; R⁴, R⁶, and R⁷ are independentlyselected from the group consisting of hydrogen, halogen, hydroxy, alkyl,haloalkyl, hydroxyalkyl, and alkoxy; R⁵ is selected from the groupconsisting of hydrogen, —(CH₂)_(m)OR⁵⁰, —(CH₂)_(m)C(O)R⁵⁰,—(CH₂)_(m)C(O)OR⁵⁰, —(CH₂)_(m)C(O)NR⁵¹R⁵², —(CH₂)_(m)NR⁵¹R⁵²,—(CH₂)_(m)N(R⁵¹)C(O)R⁵², and —(CH₂)_(m)S(O)_(m)R⁵³; m is 0, 1, 2, 3, 4,5, or 6; n is 0, 1, or 2; R⁵⁰ is selected from the group consisting ofhydrogen and alkyl; R⁵¹ and R⁵² are independently selected from thegroup consisting of hydrogen and alkyl; or R⁵¹ and R⁵² together with thenitrogen to which they are attached form a five- or six-membered ringheterocyclyt; wherein the R⁵⁰, R⁵¹ and R⁵² alkyl substituents and theR⁵¹/R⁵² heterocyclyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, pyrrolidinyl, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³,—C(O)NR⁵⁴R⁵⁵, —NR⁵⁴R⁵⁵, —N(R⁵⁸)C(O)R⁵³; —S(O)_(p)R⁵³, and—S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1, or 2; R⁵³ is selected from the groupconsisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, andcarboxyalkyl; R⁵⁴ and R⁵⁵ are independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, andcarboxyalkyl; or R⁵⁴ and R⁵⁵ together with the nitrogen to which theyare attached form a five- or six-membered ring heterocyclyl; R⁵⁶ isselected from the group consisting of hydrogen and alkyl; and R⁸ isselected from the group consisting of phenyl, pyridinyl and pyrimidinyl;wherein the phenyl, pyridinyl and pyrimidinyl substituents may beoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, carboxy,alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxy,haloalkoxy, cyanoalkoxy, amino, alkylamino, dialkylamino, andalkoxycarbonyl with the proviso that2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid is not included. 2-66. (canceled)
 67. A compound, or apharmaceutically acceptable salt of the compound, wherein the compoundhas the structure of Formula II:

wherein: X is selected from the group consisting of —CH₂— and —O—; Z isselected from the group consisting of —C(R⁸¹)— and —N—; R¹ is selectedfrom the group consisting of cyclopentyl and phenyl; wherein the R¹cyclopentyl and phenyl substituents may be optionally substituted withone or more substituents independently selected from the groupconsisting of chloro, fluoro, methyl, ethyl, propyl, chloromethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl andtrifluoromethyl; R² is selected from the group consisting of hydrogen or(C₁-C₄)-alkyl; R⁵ is selected from the group consisting of—(CH₂)_(m)OR⁵⁰, —(CH₂)_(m)C(O)OR⁵⁰, and —(CH₂)_(m)C(O)NR⁵¹R⁵²; wherein:m is 0, 1, 2, or 3; R⁵⁰ is selected from the group consisting ofhydrogen and (C₁-C₆)-alkyl; R⁵¹ and R⁵² are independently selected fromthe group consisting of hydrogen and (C₁-C₆)-alkyl; wherein the R⁵⁰, R⁵¹and R⁵² (C₁-C₆)-alkyl substituents may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁵)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1or 2; R⁵³ is selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; R⁵⁴ and R⁵⁵ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl; and R⁸¹, R⁸², R⁸³,R⁸⁴, and R⁸⁵ are independently selected from the group consisting ofhydrogen, chloro, fluoro, cyano, hydroxy, carboxy, methyl, ethyl,trichloromethyl, trifluoromethyl, cyanomethyl, hydroxymethyl,carboxymethyl, methoxy, amino, methylamino, and dimethylamino with theproviso that2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[o]indazole-7-carboxylicacid is not included.
 68. (canceled)
 69. A compound according to claim67, wherein R² is hydrogen.
 70. A compound according to claim 69,wherein: R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein: m is 0, 1, 2, or 3; R⁵⁰ isselected from the group consisting of hydrogen and (C₁-C₆)-alkyl;wherein the R⁵⁰ (C₁-C₆)-alkyl substituent may be independently andoptionally substituted with one or more substituents selected from thegroup consisting of halogen, —OR⁵³, —C(O)R⁵³, —C(O)OR⁵³, —C(O)NR⁵⁴R⁵⁵,—NR⁵⁴R⁵⁵, —N(R⁵⁸)C(O)R⁵³; —S(O)_(p)R⁵³, and —S(O)_(p)NR⁵⁴R⁵⁵; p is 0, 1or 2; R⁵³ is selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl, andcarboxy-(C₁-C₆)-alkyl; and R⁵⁴ and R⁵⁵ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, halo-(C₁-C₆)-alkyl,hydroxy-(C₁-C₆)-alkyl, and carboxy-(C₁-C₆)-alkyl.
 71. A compoundaccording to claim 69, wherein: R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein: m is0, 1, or 2; R⁵⁰ is selected from the group consisting of hydrogen and(C₁-C₄)-alkyl; wherein the R⁵⁰ (C₁-C₄)-alkyl substituent may beindependently and optionally substituted with one or more substituentsselected from the group consisting of halogen, —OR⁵³, —C(O)R⁵³, and—C(O)OR⁵³; and R⁵³ is selected from the group consisting of hydrogen and(C₁-C₄)-alkyl.
 72. A compound according to claim 69, wherein: Z isselected from the group consisting of —C(R⁸¹)— and —N—; R¹ is selectedfrom the group consisting of cyclopentyl and phenyl; wherein the R¹cyclopentyl and phenyl substituents may be optionally substituted withone or more substituents independently selected from the groupconsisting of chloro, fluoro, methyl, and trifluoromethyl; R⁵ is—(CH₂)_(m)C(O)OR⁵⁰; wherein: m is 0, 1, or 2; R⁵⁰ is selected from thegroup consisting of hydrogen and (C₁-C₄)-alkyl; wherein the R⁵⁰(C₁-C₄)-alkyl substituent may be independently and optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR⁵³, —C(O)R⁵³, and —C(O)OR⁵³; and R⁵³ isselected from the group consisting of hydrogen and (C₁-C₄)-alkyl; andR⁸¹, R⁸², R⁸³, R⁸⁴ and R⁸⁵ are independently selected from the groupconsisting of hydrogen, chloro, fluoro, cyano, hydroxy, carboxy, methyl,ethyl, cyanomethyl, hydroxymethyl, carboxymethyl, methoxy, amino,methylamino, and dimethylamino.
 73. A compound according to claim 69,wherein: Z is selected from the group consisting of —C(R⁸¹)— and —N—; R¹is selected from the group consisting of cyclopentyl and phenyl; whereinthe R¹ cyclopentyl and phenyl substituents may be optionally substitutedwith fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein: m is 0; R⁵⁰ is selectedfrom the group consisting of hydrogen and (C₁-C₄)-alkyl; and R⁸¹ and R⁸⁵are each hydrogen; and R⁸², R⁸³, and R⁸⁴ are independently selected fromthe group consisting of chloro, cyano, and methyl.
 74. A compoundaccording to claim 69, wherein: X is —CH₂—; Z is —C(R⁸¹)—; R¹ isselected from the group consisting of cyclopentyl and phenyl; whereinthe R¹ phenyl substituent may be optionally substituted with fluoro; R⁵is —(CH₂)_(m)C(O)OR⁵⁰; wherein: m is 0; R⁵⁰ is hydrogen; R⁸¹, R⁸⁴ andR⁸⁵ are each hydrogen; and R⁸² and R⁸³ are independently selected fromthe group consisting of chloro, cyano, and methyl.
 75. A compoundaccording to claim 74, wherein R⁸² is selected from the group consistingof chloro and methyl; and R⁸³ is cyano.
 76. A compound according toclaim 74, wherein R⁸² is chloro and R⁸³ is cyano.
 77. A compoundaccording to claim 74, wherein R¹ is cyclopentyl.
 78. A compoundaccording to claim 74, wherein R¹ is phenyl; wherein the R¹ phenylsubstituent may be optionally substituted with fluoro.
 79. A compoundaccording to claim 74, wherein R¹ is phenyl; wherein the R¹ phenylsubstituent may be optionally substituted with fluoro at the paraposition.
 80. A compound according to claim 69, wherein: X is —O—; Z is—C(R⁸¹)—; R¹ is selected from the group consisting of cyclopentyl andphenyl; wherein the R¹ phenyl substituent may be optionally substitutedwith fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein: m is 0; R⁵⁰ is hydrogen;R⁸¹, R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² and R⁸³ are independentlyselected from the group consisting of chloro, cyano, and methyl.
 81. Acompound according to claim 80, wherein R⁸² is selected from the groupconsisting of chloro and methyl; and R⁸³ is cyano.
 82. (canceled)
 83. Acompound according to claim 80, wherein R¹ is cyclopentyl. 84-85.(canceled)
 86. A compound according to claim 69, wherein: X is —CH₂—; Zis —N—; R¹ is selected from the group consisting of cyclopentyl andphenyl; wherein the R¹ phenyl substituent may be optionally substitutedwith fluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵³; wherein: m is 0; R⁵⁰ is hydrogen;R⁸¹, R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² and R⁸³ are independentlyselected from the group consisting of chloro, cyano, and methyl. 87.-91.(canceled)
 92. A compound according to claim 69, wherein: X is —O—; Z is—N—; R¹ is selected from the group consisting of cyclopentyl and phenyl;wherein the R¹ phenyl substituent may be optionally substituted withfluoro; R⁵ is —(CH₂)_(m)C(O)OR⁵⁰; wherein: m is 0; R⁵⁰ is hydrogen; R⁸¹,R⁸⁴ and R⁸⁵ are each hydrogen; and R⁸² and R⁸³ are independentlyselected from the group consisting of chloro, cyano, and methyl. 93.-97.(canceled)
 98. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 99.The composition of claim 98, further comprising a therapeuticallyeffective amount of one or more compounds selected from the groupconsisting of diuretics, angiotensin converting enzyme inhibitors,angiotensin II receptor blockers, calcium channel blockers, betablockers, alpha blockers, alpha-beta blockers, aldosterone receptorantagonists and renin inhibitors.
 100. The composition of claim 99,wherein the diuretics are selected from the group consisting of loopdiuretics, thiazide-type diuretics, phthalamide-type diuretics,quinazoline-type diuretics and potassium sparing diuretics. 101.-110.(canceled)
 111. A method of treating a condition selected from the groupconsisting of cardiovascular conditions, renal conditions, liverconditions, vascular conditions, inflammatory conditions, pain,retinopathy, neuropathy (such as peripheral neuropathy), Insulinopathy,edema, endothelial dysfunction and baroreceptor dysfunction comprisingadministering a therapeutically effective amount of a compound of claim1 to a subject in need thereof. 112.-113. (canceled)
 114. The method ofclaim 111, wherein the cardiovascular condition is hypertension. 115.(canceled)
 116. The method of claim 111, wherein the renal condition isnephrapathy.
 117. A compound, or a pharmaceutically acceptable salt ofthe compound, selected from the group consisting of:2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-methylbenzonitrile;3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)-2-(trifluoromethyl)benzonitrile;2-chloro-4-(3-(4-fluorophenyl)-7-hydroxy-3,3a,4,5-tetrahydrobenzo[g]indazol-2-yl)benzonitrile;2-(3-Chloro-4-cyanophenyl)-3-(4-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;2-(4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(5-cyano-6-methylpyridin-2-yl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;N-(−2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide;methyl2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate;2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3a-methyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-hydroxyethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid;2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid.2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(3-chloro-4-cyanophenyl)-3-(3-furyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylicacid;2-(3-chloro-4-cyanophenyl)-3-(5-methyl-2-fury))-N-[2-(methylsulfonyl)ethyl]-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;2-(3-chloro-4-cyanophenyl)-N-[2-(methylsulfonyl)ethyl]-3-(2-methyl-1,3-thiazol-5-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide;2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid;2-[4-cyano-3-(trifluoromethyl)phenyl-]3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid;2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid; and2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylicacid.